ORCID Profile
0000-0002-9967-0084
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Publisher: Wiley
Date: 26-05-2020
DOI: 10.1111/AJI.13260
Publisher: Oxford University Press (OUP)
Date: 12-1995
DOI: 10.1095/BIOLREPROD53.6.1407
Abstract: The rat testis contains a large population of resident macrophages, the physiological roles of which are yet to be established. To investigate the functional capacity of these cells, we have analyzed the secretion of the cytokines interleukin (IL)-1, IL-6, tumor necrosis factor alpha (TNF alpha), and granulocyte macrophage-colony stimulating factor (GM-CSF) by isolated testicular macrophages (TMs) and, for comparison, by isolated rat peritoneal macrophages (PMs). Cells were cultured for 48 h in serum-free medium alone or with lipopolysaccharide (LPS, 10 micrograms/ml) and/or recombinant interferon-gamma (rIFN gamma, 200 U/ml). Specific bioassays were used to measure cytokines in the media collected from cultures. Basal production of IL-1, TNF alpha, and IL-6 by TMs and PMs were similar, but TMs produced 8-fold greater levels of GM-CSF than did PMs. LPS, alone or in combination with IFN gamma, significantly enhanced the secretion of all cytokines by PMs (340-840% increase). LPS alone had little effect on TM secretion except to reduce GM-CSF levels some 4-fold. The addition of LPS and IFN gamma increased IL-1, IL-6, and TNF alpha levels (200-750% increase) and reduced GM-CSF levels to 45% of basal levels. Treatment of cultures with indomethacin to minimize prostaglandin production enhanced the LPS-induced effects in both cell types. Expression of the mRNA for each cytokine in cultures of testicular and peritoneal macrophages, as well as in intact testis, was confirmed by reverse transcription polymerase chain reaction. These studies indicate that macrophages resident within the rat testis have a novel cytokine secretion profile and an altered responsiveness to inflammatory activators compared with macrophages from the peritoneal cavity. This may be important in physiological processes in the testis and may contribute to the dysfunctional afferent immune activity thought to underlie the immunologically privileged status of the testes.
Publisher: Elsevier BV
Date: 03-2010
DOI: 10.1016/J.PLACENTA.2009.12.008
Abstract: Workshops are an important part of the annual meeting of the International Federation of Placenta Associations (IFPA). At IFPA Meeting 2009 erse topics were discussed in twelve themed workshops. Topics covered included: immune response to pregnancy signaling between fetus and placenta bioactive lipids in placenta placenta in agricultural species epigenetics and placentation trophoblast deportation glucocorticoids and placental function endothelium placental transport genes and placenta uteroplacental blood flow and placental stem cells. This report is a full summary of the various topics covered.
Publisher: The Endocrine Society
Date: 11-2003
DOI: 10.1210/EN.2003-0584
Publisher: Oxford University Press (OUP)
Date: 06-1992
DOI: 10.1095/BIOLREPROD46.6.1069
Abstract: Cytokine secretion by endometrial cells from estrous and mated mice was measured using specific bioassays. The granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-6 (IL-6) contents of uterine intraluminal fluid were elevated greater than 20-fold and 250-fold respectively following mating, and both cytokines were synthesized in abundance in vitro by uterine cells harvested at estrus and on Day 1 of pregnancy. Synthesis was not impaired in genetically lymphocyte-deficient nude, SCID, or beige mice. To determine the cellular origin of the cytokines, a panning technique employing monoclonal antibodies against a range of leukocyte and other lineage markers was used to isolate uterine cell subsets in vitro. These experiments identified glandular and/or luminal epithelial cells as the major source of GM-CSF and IL-6 in estrous and pregnant uteri. Stromal fibroblasts also synthesized IL-6, as did macrophages in mated mice. Epithelial cells harvested from midgestation uteri secreted GM-CSF and IL-6 in quantities similar to those of cells from estrous and mated mice. Bioactivities of both cytokines derived from epithelial cells were neutralized by specific antibodies, and size-exclusion chromatography of conditioned media from uterine cells revealed peaks of GM-CSF and IL-6 bioactivity with M(r) 23,000 and 23,000-26,000, respectively. Bioassay of luminal fluids and culture supernatants were negative for the cytokines interleukin-1, interleukin-2, interleukin-3, and tumor necrosis factor-alpha. These studies identify murine uterine epithelium as a potent source of the cytokines GM-CSF and IL-6, which we postulate have potentially important functions in pregnancy through actions on target cells in both the uterus and the conceptus.
Publisher: Elsevier BV
Date: 04-2003
Abstract: Placental morphogenesis and nutrient transfer function are regulated by growth factors at the foeto-maternal interface. Interleukin (IL)-10, expressed in the decidua and placenta, is implicated in regulating extravillous cytotrophoblast invasion through inhibiting matrix metalloproteinase expression and influencing the quality of the maternal immune response. Our laboratory has previously found that IL-10 deficiency in both the mother and foetus increases foetal weight at day 18 without altering placental weight suggesting that the placenta has a greater functional capacity when IL-10 is absent. The present study has used IL-10 null mutant (IL-10-/-) mice to investigate the role of IL-10 in placental development. Placental structure was assessed in adult virgin IL-10-/- or wild-type (IL-10+/+) mice mated with males of the same genotype and sacrificed at day 18 of gestation. Mid-sagittal cross sections of placental tissue were stained with Masson's trichrome or immuno-labelled with MTS-12 and pan-cytokeratin reactive antibodies to identify foetal endothelial cells and trophoblasts, respectively, and examined with video image analysis. IL-10 deficiency increased the total cross sectional area of the placenta by 28 per cent (IL-10-/- n=22 placentae from 8 dams, IL-10+/+n =21 placentae from 9 dams, P=0.026), principally through increasing the cross sectional area of placental labyrinth by 37 per cent (P=0.025). The proportion of maternal blood space in the labyrinth was increased by 26 per cent (P=0.001) and that of trophoblast was decreased by 16 per cent (P=0.001) in IL-10-/- placentae. The surface area of trophoblast per gram of labyrinth was increased by 41 per cent (P=0.0005) in IL-10-/- placentae. In the absence of IL-10, structural correlates of placental function are enhanced consistent with concomitant increases in foetal growth. These data indicate that IL-10 is a regulator of placental morphogenesis, acting to retard expansion of the placental labyrinth and to modify the architecture of the maternal blood sinuses. Since previous studies have paradoxically shown that postnatal growth is impaired in IL-10 null mutants, these observations are consistent with a role for IL-10 in regulating placental development and foetal programming.
Publisher: Cambridge University Press (CUP)
Date: 30-09-2016
DOI: 10.1017/S2040174416000477
Abstract: Epidemiology formed the basis of ‘the Barker hypothesis’, the concept of ‘developmental programming’ and today’s discipline of the Developmental Origins of Health and Disease (DOHaD). Animal experimentation provided proof of the underlying concepts, and continues to generate knowledge of underlying mechanisms. Interventions in humans, based on DOHaD principles, will be informed by experiments in animals. As knowledge in this discipline has accumulated, from studies of humans and other animals, the complexity of interactions between genome, environment and epigenetics, has been revealed. The vast nature of programming stimuli and breadth of effects is becoming known. As a result of our accumulating knowledge we now appreciate the impact of many variables that contribute to programmed outcomes. To guide further animal research in this field, the Australia and New Zealand DOHaD society (ANZ DOHaD) Animals Models of DOHaD Research Working Group convened at the 2nd Annual ANZ DOHaD Congress in Melbourne, Australia in April 2015. This review summarizes the contributions of animal research to the understanding of DOHaD, and makes recommendations for the design and conduct of animal experiments to maximize relevance, reproducibility and translation of knowledge into improving health and well-being.
Publisher: Springer Science and Business Media LLC
Date: 02-2018
DOI: 10.1038/S41598-018-19263-8
Abstract: Diabetes has been linked with impaired fertility but the underlying mechanisms are not well defined. Here we use a streptozotocin-induced diabetes mouse model to investigate the cellular and biochemical changes in conceptus and maternal tissues that accompany hyperglycaemia. We report that streptozotocin treatment before conception induces profound intra-cellular protein β- O -glycosylation ( O -GlcNAc) in the oviduct and uterine epithelium, prominent in early pregnancy. Diabetic mice have impaired blastocyst development and reduced embryo implantation rates, and delayed mid-gestation growth and development. Peri-conception changes are accompanied by increased expression of pro-inflammatory cytokine Trail , and a trend towards increased Il1a , Tnf and Ifng in the uterus, and changes in local T-cell dynamics that skew the adaptive immune response to pregnancy, resulting in 60% fewer anti-inflammatory regulatory T-cells within the uterus-draining lymph nodes. Activation of the heat shock chaperones, a mechanism for stress deflection, was evident in the reproductive tract. Additionally, we show that the embryo exhibits elevated hyper- O -GlcNAcylation of both cytoplasmic and nuclear proteins, associated with activation of DNA damage (ɣH2AX) pathways. These results advance understanding of the impact of peri-conception diabetes, and provide a foundation for designing interventions to support healthy conception without propagation of disease legacy to offspring.
Publisher: Bioscientifica
Date: 07-2006
DOI: 10.1530/REP.1.01119
Abstract: Seminal plasma (SP) acts to influence the uterine endometrium after mating, activating synthesis of embryotrophic cytokines and inflammatory changes that condition the tract for embryo implantation and establishing pregnancy. The objective of this study was to investigate in pigs whether the ovary might also be responsive to SP exposure. Prepubertal gilts were synchronised with exogenous gonadotrophins and received transcervical treatment with pooled boar SP or PBS then the ovarian tissue was recovered at 34 h (preovulation) and on days 5 and 9 after treatment. The ovarian response was assessed by measuring ovulation rate, number and size of corpora lutea, ovarian leukocyte populations, progesterone production in vivo , as well as responses of retrieved granulosa cells cultured in vitro . In SP-treated gilts, leukocyte recruitment into the ovarian tissues was increased fourfold at 34 h, with macrophages comprising the most abundant cell lineage. There was no effect of SP on the number of oocytes ovulated however, the weight of corpora lutea was increased in SP-treated gilts. SP also induced an increase in plasma progesterone content seen from day 5 to at least day 9 after treatment. In addition, granulosa cells and thecal tissue retrieved from preovulatory follicles of SP-treated gilts were more responsive in vitro to growth factor- and gonadotrophin-stimulated cell proliferation and progesterone synthesis. These results suggest that uterine exposure to SP influences immune cell trafficking in the ovary and enhances steroidogenesis in early pregnancy. The effects of SP on ovarian function potentially contribute to reproductive success in the pig.
Publisher: The American Association of Immunologists
Date: 15-07-2018
Abstract: Immune cells adapt their phenotypic and functional characteristics in response to the tissue microenvironment within which they traffic and reside. The fetomaternal interface, consisting of placental trophoblasts and the maternal decidua, is a highly specialized tissue with a unique and time-limited function: to nourish and support development of the semiallogeneic fetus and protect it from inflammatory or immune-mediated injury. It is therefore important to understand how immune cells within these tissues are educated and adapt to fulfill their biological functions. This review article focuses on the local regulatory mechanisms ensuring that both innate and adaptive immune cells appropriately support the early events of implantation and placental development through direct involvement in promoting immune tolerance of fetal alloantigens, suppressing inflammation, and remodeling of maternal uterine vessels to facilitate optimal placental function and fetal growth.
Publisher: Elsevier BV
Date: 09-2009
Publisher: American Society for Clinical Investigation
Date: 10-2018
DOI: 10.1172/JCI122182
Publisher: Wiley
Date: 2018
DOI: 10.1002/CTI2.1011
Publisher: Bentham Science Publishers Ltd.
Date: 18-05-2018
DOI: 10.2174/1381612824666180130122450
Abstract: Inflammatory activation, a major driver of preterm birth and subsequent neonatal morbidity, is an attractive pharmacological target for new preterm birth therapeutics. Inflammation elicited by intraamniotic infection is causally associated with preterm birth, particularly in infants delivered ≤34 weeks’ gestation. However, sterile triggers of PTB, including placental ischaemic injury, uterine distention, cervical disease, or imbalance in the immune response, also act through inflammatory mediators released in response to tissue damage. Toll-like Receptors (TLRs) are critical upstream gate-keepers controlling the inflammatory activation that precedes preterm delivery, as well as in normal term labour. In particular, TLR4 is implicated for its capacity to sense and integrate a range of disparate infectious and sterile pro-inflammatory triggers, and so acts as a point-ofconvergence through which a range of infectious and sterile agents can activate and accelerate the parturition cascade. Recent studies point to the TLR4 signalling complex as a tractable target for the inhibition of fetal, placental & intraamniotic inflammatory cytokine production. Moreover, studies on mice show that novel small molecule antagonists of TLR4 signalling are highly effective in preventing preterm birth induced by bacterial mimetic LPS, heat-killed E. coli or the TLR4-dependent pro-inflammatory lipid, Platelet Activating Factor (PAF). In this review, we discuss the role of TLR4 in regulating the timing of birth and the potential utility of TLR4 antagonists as novel therapeutics for preterm delivery.
Publisher: Oxford University Press (OUP)
Date: 03-2000
DOI: 10.1095/BIOLREPROD62.3.704
Abstract: During the estrous cycle and early pregnancy, lymphohemopoietic cytokines and chemokines contribute to the regulation of ovarian function by orchestrating the recruitment and activation of leukocytes associated with the ovulatory follicle and corpus luteum. The purpose of this study was to investigate the physiological role of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the ovary, utilizing mice genetically deficient in GM-CSF. Our results show that the mean duration of the estrous cycle in GM-CSF-deficient (GM-/-) mice was extended by 1.5 days (mean +/- SE, 4.9 +/- 0.3 vs. 6.5 +/- 0.5 days for GM+/+ and GM-/- mice, respectively). Similar ovulation rates were observed in immature superovulated mice (31.8 +/- 7.7 vs. 28.9 +/- 6.4 oocytes per mouse) and adult naturally cycling mice (10.4 +/- 0.8 vs. 10.3 +/- 0.8 oocytes per mouse). Furthermore, comparable numbers of oocytes were released from GM+/+ and GM-/- ovaries in an in vitro perfusion model. However, ovaries in pregnant GM-/- mice were found to comprise fewer cells and synthesize less progesterone (141.6 +/- 10.3 vs. 116.5 +/- 6 nM plasma), although the duration of pseudopregnancy was unaltered by GM-CSF deficiency (11.0 +/- 0.2 vs. 11.0 +/- 0.5 days). Immunohistochemical staining of leukocytes in the ovary during the periovulatory period indicated that the size and composition of ovarian leukocyte populations were unaltered in the absence of GM-CSF. However, an effect of GM-CSF deficiency on the activation phenotype of ovarian leukocytes was indicated by a 57% increase in mean secretion of nitric oxide in in vitro-perfused GM-/- ovaries, and diminished major histocompability complex (MHC) class II (Ia) expression in ovarian macrophages and/or dendritic cells (30.5 +/- 7. 2% vs. 9.1 +/- 1.8% positive stain in GM+/+ and GM-/- ovaries, respectively). Furthermore, ovarian macrophages and neutrophils were diminished in number after parturition, with significantly decreased CD11b+ (Mac-1) staining in the stromal region of postpartum GM-/- ovaries (6.7 +/- 0.6 vs. 3.6 +/- 0.7% positive stain). In summary, GM-CSF does not appear to be essential for ovarian function but may play a role in fine-tuning the activation status and adhesive properties of ovarian myeloid leukocytes. Aberrant activation of these cells appears to compromise the luteinization process and the steroidogenic capacity of the corpus luteum during early pregnancy in GM-CSF-deficient mice.
Publisher: Wiley
Date: 2022
DOI: 10.1002/CTI2.1377
Abstract: Transfusion with washed packed red blood cells (PRBCs) may be associated with reduced transfusion‐related pro‐inflammatory cytokine production. This may be because of alterations in recipient immune responses. This randomised trial evaluated the effect of transfusion with washed compared with unwashed PRBCs on pro‐inflammatory cytokines and endothelial activation in 154 preterm newborns born before 29 weeks’ gestation. Changes in plasma cytokines and measures of endothelial activation in recipient blood were analysed after each of the first three transfusions. By the third transfusion, infants receiving unwashed blood had an increase in IL‐17A ( P = 0.04) and TNF ( P = 0.007), whereas infants receiving washed blood had reductions in IL‐17A ( P = 0.013), TNF ( P = 0.048), IL‐6 ( P = 0.001), IL‐8 ( P = 0.037), IL‐12 ( P = 0.001) and IFN‐γ ( P = 0.001). The magnitude of the post‐transfusion increase in cytokines did not change between the first and third transfusions in the unwashed group but decreased in the washed group for IL‐12 ( P = 0.001), IL‐17A ( P = 0.01) and TNF ( P = 0.03), with the difference between the groups reaching significance by the third transfusion ( P 0.001 for each cytokine). The pro‐inflammatory immune response to transfusion in preterm infants can be modified when PRBCs are washed prior to transfusion. Further studies are required to determine whether the use of washed PRBCs for neonatal transfusion translates into reduced morbidity and mortality.
Publisher: Oxford University Press (OUP)
Date: 11-03-2020
Abstract: Corticosteroids have been utilised in the assisted reproduction setting with the expectation of suppressing aberrant immune activation and improving fertility in women. However, the effects of corticosteroids on fertility, and on pregnancy and offspring outcomes, are unclear. In this study, mice were administered prednisolone (1 mg/kg) or PBS daily in the pre-implantation phase, and effects on the adaptive immune response, the implantation rate, fetal development and postnatal outcomes were investigated. Prednisolone disrupted the expected expansion of CD4+ T cells in early pregnancy, inhibiting generation of both regulatory T cells (Treg cells) and effector T cells and suppressing IFNG required for T cell functional competence. Prednisolone caused an 8–20% increase in the embryo implantation rate and increased the number of viable pups per litter. In late gestation, fetal and placental weights were reduced in a litter size-dependent manner, and the canonical inverse relationship between litter size and fetal weight was lost. The duration of pregnancy was extended by ~ 0.5 day and birth weight was reduced by ~ 5% after prednisolone treatment. Viability of prednisolone-exposed offspring was comparable to controls, but body weight was altered in adulthood, particularly in male offspring. Thus, while prednisolone given in the pre-implantation phase in mice increases maternal receptivity to implantation and resource investment in fetal growth, there is a trade-off in long-term consequences for fetal development, birth weight and offspring health. These effects are associated with, and likely caused by, prednisolone suppression of the adaptive immune response at the outset of pregnancy.
Publisher: Oxford University Press (OUP)
Date: 08-09-2016
Abstract: Do seminal plasma transforming growth factor-β (TGFB) cytokines vary within in iduals over time, and does this relate to sperm parameters, age or prior abstinence? Activin A and follistatin, and to a lesser extent TGFB1, TGFB2 and TGFB3, vary within in iduals over time, in association with duration of abstinence. Seminal plasma TGFB cytokines can influence sperm function and reproductive success through interactions with the female reproductive tract after coitus. Over time, in idual sperm parameters fluctuate considerably. Whether seminal fluid TGFB cytokines vary similarly, and the determinants of any variance, is unknown. Between two and seven semen s les were collected from each of 14 fertile donors at 6-10 week intervals over the course of 12 months, then seminal plasma cytokines and sperm parameters were measured. The concentrations and total amounts per ejaculate of TGFB1, TGFB2, TGFB3, activin A and follistatin were determined using commercial assays. Sperm parameters were assessed according to WHO IV standards. Mixed model analysis was utilised to determine the relative contribution of between- and within-in idual factors to the variance. Relationships between cytokines and sperm parameters, as well as effect of age and duration of abstinence, were investigated by correlation analysis. Within-in idual variability contributed to the total variance for all cytokines and sperm parameters, and was a stronger determinant than between-in idual variability for activin A and follistatin as well as for total sperm concentration and sperm motility. Positive correlations between each of the three TGFB isoforms, and activin and follistatin, suggest co-regulation of synthesis. Duration of abstinence influenced total content of TGFB1, TGFB2, activin A and follistatin. TGFB1 correlated inversely with age. A limited number of donors from a single clinic were investigated. Clinical information on BMI, nutrition, smoking and other lifestyle factors was unavailable. Further studies are required to determine whether the findings can be generalised to larger populations and different ethnicities. These data reveal substantial variation over time in seminal fluid cytokines and indicate that repeated analyses are required to gain precise representative data on an in idual's status. Within-in idual variation in seminal fluid components should be taken into account when investigating seminal fluid cytokines. This study was supported by grants from the National Health and Medical Research Council of Australia, ID453556 and APP1041332. The authors have no competing interests to disclose.
Publisher: Oxford University Press (OUP)
Date: 02-09-2016
Abstract: There is ongoing interest in immune-suppressant corticosteroid drugs such as prednisolone to treat infertility in women with repeated IVF failure and recurrent miscarriage. The rationale draws on the pervasive but flawed view that immune activation is inconsistent with normal pregnancy. This ignores clear evidence that controlled inflammation and activation of the immune response is essential for embryo implantation. Generally, the immune response actively promotes reproductive success - by facilitating endometrial receptivity and tolerance of the foreign embryo, and promoting vascular adaptation to support placental morphogenesis. The peri-conception immune response also establishes developmental trajectories that can impact on fetal growth and gestational age at birth. Here, we describe immune changes accompanying conception that could be impeded by inappropriate corticosteroid administration. While women with specific clinical conditions may benefit from the anti-inflammatory and immune-deviating actions of prednisolone and related drugs, it is incorrect to assume a 'one-size-fits-all' approach. Better diagnostics and more preclinical studies are essential to define patient groups, build evidence for efficacy and fine-tune treatments so as not to inhibit essential actions of immune cells. We argue that unless overt immune pathology is evident, utilization of corticosteroids is not warranted and may be harmful. In most women, perturbing immune adaptation at implantation is expected to adversely influence placental development and impair immune-mediated quality control mechanisms, potentially elevating risk of altered fetal growth and developmental programming, congenital anomalies and preterm birth.
Publisher: MyJove Corporation
Date: 21-05-2015
DOI: 10.3791/52866
Publisher: Wiley
Date: 27-02-2018
DOI: 10.1111/AJI.12835
Publisher: Elsevier BV
Date: 08-1997
Publisher: The Endocrine Society
Date: 07-07-2015
DOI: 10.1210/EN.2015-1089
Abstract: An inflammatory response is instrumental in the physiological process of parturition but the upstream signals initiating inflammation are undefined. Because endogenous ligands for Toll-like receptor 4 (TLR4) are released in late gestation, we hypothesized that on-time labor requires TLR4 signaling, to trigger a cytokine and leukocyte response and accelerate the parturition cascade. In pregnant TLR4-deficient (Tlr4−/−) mice, average gestation length was extended by 13 hours and increased perinatal mortality was seen compared with wild-type controls. Quantification of cytokine and uterine activation gene expression showed that late gestation induction of Il1b, Il6, Il12b, and Tnf expression seen in control placenta and fetal membranes was disrupted in Tlr4−/− mice, and accompanied by a transient delay in expression of uterine activation genes, including prostaglandin F receptor, oxytocin receptor, and connexin-43. Leukocyte populations were altered before birth in TLR4-deficient females, with fewer neutrophils and macrophages in the placenta, and fewer dendritic cells and more regulatory T cells in the myometrium. Administration of TLR4 ligand lipopolysaccharide to pregnant wild-type mice induced cytokine expression and fetal loss, whereas Tlr4−/− pregnancies were protected. The small molecule TLR4 antagonist (+)-naloxone increased mean duration of gestation by 16 hours in wild-type mice. Collectively, these data demonstrate that TLR4 is a key upstream regulator of the inflammatory response acting to drive uterine activation and control the timing of labor. Because causal pathways for term and preterm labor converge with TLR4, interventions to manipulate TLR4 signaling may have therapeutic utility for women at risk of preterm labor, or in postterm pregnancy.
Publisher: Wiley
Date: 31-05-2016
DOI: 10.1038/ICB.2016.48
Abstract: Compared with lymphoid tissues, the immune cell compartment at mucosal sites is enriched with T cells bearing the γδ T-cell receptor (TCR). The female reproductive tract, along with the placenta and uterine decidua during pregnancy, are populated by γδ T cells predominantly expressing the invariant Vγ6(+)Vδ1(+) receptor. Surprisingly little is understood about the function of these cells. We found that the majority of γδ T cells in the non-pregnant uterus, pregnant uterus, decidua and placenta of mice express the transcription factor RORγt and produce interleukin-17 (IL-17). In contrast, IFNγ-producing γδ T cells were markedly reduced in gestational tissues compared with uterine-draining lymph nodes and spleen. Both uterine-resident invariant Vγ6(+) and Vγ4(+) γδ T cells which are more typically found in lymphoid tissues and circulating blood, were found to express IL-17. Vγ4(+) γδ T cells were particularly enriched in the placenta, suggesting a pregnancy-specific recruitment or expansion of these cells. A small increase in IL-17-producing γδ T cells was observed in allogeneic compared with syngeneic pregnancy, suggesting a contribution to regulating the maternal response to paternally-derived alloantigens. However, their high proportions also in non-pregnant uteri and gestational tissues of syngeneic pregnancy imply a role in the prevention of intrauterine infection or quality control of fetal development. These data suggest the need for a more rigorous evaluation of the role of IL-17 in sustaining normal pregnancy, particularly as emerging data points to a pathogenic role for IL-17 in pre-ecl sia, pre-term birth, miscarriage and maternal immune activation-induced behavioral abnormalities in offspring.
Publisher: Oxford University Press (OUP)
Date: 19-04-2018
DOI: 10.1093/HMG/DDY139
Publisher: Frontiers Media SA
Date: 20-01-2022
DOI: 10.3389/FVETS.2021.819246
Abstract: The classical view of “pheromone”—an air-borne chemical signal—is challenged by the camelids in which ovulation is triggered by ß-nerve growth factor carried in seminal plasma, effectively extending the pheromone concept to a new medium. We propose further extension of “pheromone” to include a separate class of seminal fluid molecules that acts on the female reproductive tract to enhance the prospect of pregnancy. These molecules include transforming growth factor-ß, 19-OH prostaglandins, various ligands of Toll-like receptor-4 (TLR4), and cyclic ADP ribose hydrolase (CD38). They modulate the immune response to “foreign” male-derived histocompatibility antigens on both sperm and the conceptus, determine pre-implantation embryo development, and then promote implantation by increasing uterine receptivity to the embryo. The relative abundance of these immunological molecules in seminal plasma determines the strength and quality of the immune tolerance that is generated in the female. This phenomenon has profound implications in reproductive biology because it provides a pathway, independent of the fertilizing sperm, by which paternal factors can influence the likelihood of reproductive success, as well as the phenotype and health status of offspring. Moreover, the female actively participates in this exchange—information in seminal fluid is subject to “cryptic female choice,” a process by which females interrogate the reproductive fitness of prospective mates and invest reproductive resources accordingly. These processes participate in driving the evolution of male accessory glands, ensuring optimal female reproductive investment and maximal progeny fitness. An expanded pheromone concept will avoid a constraint in our understanding of mammalian reproductive biology.
Publisher: Elsevier BV
Date: 02-2018
DOI: 10.1016/J.JRI.2017.12.003
Abstract: Cytokines in the reproductive tract environment at conception mediate a dialogue between the embryo and maternal tissues to profoundly influence embryo development and implantation success. Through effects on gene expression and the cell stress response, cytokines elicit an epigenetic impact with consequences for placental development and fetal growth, which in turn affect metabolic phenotype and long-term health of offspring. There is substantial evidence demonstrating that pro-survival cytokines, such as GM-CSF, CSF1, LIF, HB-EGF and IGFII, support embryos to develop optimally. Less attention has been paid to cytokines that adversely impact embryo development, including the pro-inflammatory cytokines TNF, TRAIL and IFNG. These agents elicit cell stress, impair cell survival and retard blastocyst development, and at sufficiently high concentrations, can cause embryo demise. Experiments in mice suggest these so-called 'embryotoxic' cytokines can harm embryos through pro-apoptotic and adverse programming effects, as well as indirectly suppressing uterine receptivity through the maternal immune response. Embryotrophic factors may mitigate against and protect from these adverse effects. Thus, the balance between embryotrophic and embryotoxic cytokines can impart effects on embryo development and implantation, and has the potential to contribute to endometrial 'biosensor' function to mediate embryo selection. Embryotoxic cytokines can be elevated in plasma and reproductive tract tissues in inflammatory conditions including infection, diabetes, obesity, PCOS and endometriosis. Studies are therefore warranted to investigate whether excessive embryotoxic cytokines contribute to infertility and recurrent implantation failure in women, and compromised reproductive performance in livestock animals.
Publisher: Bioscientifica
Date: 03-2019
DOI: 10.1530/EC-18-0502
Abstract: Many complex diseases exhibit co-morbidities often requiring management by more than one health specialist. We examined cross-speciality issues that ultimately affect the health and wellbeing of patients with polycystic ovary syndrome (PCOS). PCOS was originally described as a reproductive condition but is now recognised to also be a metabolic and psychological condition affecting 8–13% of women of reproductive age. With a four-fold increased risk of type 2 diabetes (DM2), the Population Attributable Risk of DM2 that could be avoided if PCOS were eliminated is a substantial 19–28% of women of reproductive age. To determine the extent to which PCOS is an important consideration in diabetes development, we examined publications, funding, guidelines and predictors of risk of developing DM2. We found that the topic of PCOS appeared in specialist diabetes journals at only 10% the rate seen in endocrinology journals – about 1 in 500 articles. We found research funding to be substantially less than for diabetes and found that diabetes guidelines and predictive tools for DM2 risk mostly ignore PCOS. This is surprising since insulin resistance in women with PCOS has a different aetiology and additionally women with PCOS are at increased risk of becoming overweight or obese – high risk factors for DM2. We consider the causes of these concerning anomalies and discuss current activities to address the co-morbidities of PCOS, including the recent development of international guidelines, an international PCOS awareness program and potentially changing the name of PCOS to better reflect its metabolic consequences.
Publisher: Wiley
Date: 2020
DOI: 10.1002/CTI2.1121
Publisher: Oxford University Press (OUP)
Date: 05-05-2007
Abstract: Exposure to semen elicits an inflammatory response in the female reproductive tract of rodents and other animals. The nature and regulation of any similar response in humans is poorly understood. This study investigated seminal plasma induction of inflammatory cytokine and chemokine gene regulation in human cervical and vaginal epithelial cells in vitro. Affymetrix microarray gene profiling revealed that inflammatory cytokine genes were prevalent among 317 known genes differentially expressed in immortalized ectocervical epithelial (Ect1) cells after incubation with pooled human seminal plasma. A dose- and time-dependent induction by seminal plasma of IL8, IL6, CSF2 and CCL2 mRNA expression in Ect1 cells was verified by quantitative RT-PCR. This was accompanied by increases in Ect1 secretion of immunoactive gene products IL-8, IL-6, GM-CSF and MCP-1. Similar cytokine responses were elicited in primary ectocervical epithelial cells. Endocervical epithelial (End1) and vaginal epithelial (Vk2) cells were less responsive to seminal fluid, with induction of IL-8 and MCP-1, but not GM-CSF or IL-6. In a panel of 10 seminal plasma s les, considerable variation in inflammatory cytokine-inducing activity was evident. These experiments show that seminal plasma can elicit expression of a range of inflammatory cytokines and chemokines in reproductive tract epithelia, and implicate the ectocervix as the primary site of responsiveness, with gene-specific differences in the kinetics and site-restrictedness of the response. Seminal factor regulation of inflammatory cytokines in the cervical epithelium is implicated in controlling the immune response to seminal antigens, and defence against infectious agents introduced at intercourse.
Publisher: The American Association of Immunologists
Date: 15-07-2012
Abstract: The cervix is central to the female genital tract immune response to pathogens and foreign male Ags introduced at coitus. Seminal fluid profoundly influences cervical immune function, inducing proinflammatory cytokine synthesis and leukocyte recruitment. In this study, human Ect1 cervical epithelial cells and primary cervical cells were used to investigate agents in human seminal plasma that induce a proinflammatory response. TGF-β1, TGF-β2, and TGF-β3 are abundant in seminal plasma, and Affymetrix microarray revealed that TGF-β3 elicits changes in Ect1 cell expression of several proinflammatory cytokine and chemokine genes, replicating principal aspects of the Ect1 response to seminal plasma. The differentially expressed genes included several induced in the physiological response of the cervix to seminal fluid in vivo. Notably, all three TGF-β isoforms showed comparable ability to induce Ect1 cell expression of mRNA and protein for GM-CSF and IL-6, and TGF-β induced a similar IL-6 and GM-CSF response in primary cervical epithelial cells. TGF-β neutralizing Abs, receptor antagonists, and signaling inhibitors ablated seminal plasma induction of GM-CSF and IL-6, but did not alter IL-8, CCL2 (MCP-1), CCL20 (MIP-3α), or IL-1α production. Several other cytokines present in seminal plasma did not elicit Ect1 cell responses. These data identify all three TGF-β isoforms as key agents in seminal plasma that signal induction of proinflammatory cytokine synthesis in cervical cells. Our findings suggest that TGF-β in the male partner’s seminal fluid may influence cervical immune function after coitus in women, and potentially be a determinant of fertility, as well as defense from infection.
Publisher: American Chemical Society (ACS)
Date: 09-12-2014
DOI: 10.1021/CB5007163
Abstract: Phenotypic screening of a quinoxaline library against replicating Mycobacterium tuberculosis led to the identification of lead compound Ty38c (3-((4-methoxybenzyl)amino)-6-(trifluoromethyl)quinoxaline-2-carboxylic acid). With an MIC99 and MBC of 3.1 μM, Ty38c is bactericidal and active against intracellular bacteria. To investigate its mechanism of action, we isolated mutants resistant to Ty38c and sequenced their genomes. Mutations were found in rv3405c, coding for the transcriptional repressor of the ergently expressed rv3406 gene. Biochemical studies clearly showed that Rv3406 decarboxylates Ty38c into its inactive keto metabolite. The actual target was then identified by isolating Ty38c-resistant mutants of an M. tuberculosis strain lacking rv3406. Here, mutations were found in dprE1, encoding the decaprenylphosphoryl-d-ribose oxidase DprE1, essential for biogenesis of the mycobacterial cell wall. Genetics, biochemical validation, and X-ray crystallography revealed Ty38c to be a noncovalent, noncompetitive DprE1 inhibitor. Structure-activity relationship studies generated a family of DprE1 inhibitors with a range of IC50's and bactericidal activity. Co-crystal structures of DprE1 in complex with eight different quinoxaline analogs provided a high-resolution interaction map of the active site of this extremely vulnerable target in M. tuberculosis.
Publisher: Elsevier BV
Date: 09-2016
DOI: 10.1016/J.FERTNSTERT.2016.07.1101
Abstract: Seminal fluid is often viewed as simply a vehicle to carry sperm to fertilize the oocyte, but a more complex function in influencing female reproductive physiology is now evident. Remarkably, seminal fluid contains soluble and exosome-born signaling agents that interact with the female reproductive tract to prime the immune response, with consequences for fertility and pregnancy outcome. Experiments in rodent models demonstrate a key role for seminal fluid in enabling robust embryo implantation and optimal placental development. In particular, seminal fluid promotes leukocyte recruitment and generation of regulatory T cells, which facilitate embryo implantation by suppressing inflammation, assisting uterine vascular adaptation, and sustaining tolerance of fetal antigens. There is emerging evidence of comparable effects in women, where seminal fluid provokes an adaptive immune response in the cervical tissues after contact at intercourse, and spermatozoa accessing the higher tract potentially affect the endometrium directly. These biological responses may have clinical significance, explaining why [1] intercourse in IVF ET cycles improves the likelihood of pregnancy, [2] inflammatory disorders of gestation are more common in women who conceive after limited exposure to seminal fluid of the prospective father, and [3] preecl sia incidence is elevated after use of donor oocytes or donor sperm where prior contact with conceptus alloantigens has not occurred. It will be important to define the mechanisms through which seminal fluid interacts with female reproductive tissues, to provide knowledge that may assist in preconception planning and infertility treatment.
Publisher: Bioscientifica
Date: 09-2000
Abstract: The uterine immune axis holds the key to solving major problems in female reproductive health, including infertility, many pathologies of pregnancy, and sexually transmitted disease. The molecular determinants of tolerance and immunity in the reproductive tract are now being identified, and the governing principles are similar to those in other mucosal tissues. Cytokines are implicated as pivotal regulators at important 'decision-making' points in each phase of the induction and elicitation of a response. Indeed, the flexibility to deal appropriately with antigens as disparate as infectious micro-organisms, spermatozoa and the conceptus is likely to be attributable to the sophistication of the cytokine network in driving immune deviation. A better understanding of the factors controlling the development of immune activity in the uterus, particularly the significance of the inductive cytokine environment in determining the destiny of T-lymphocyte responses, will assist the rational design of new therapeutic strategies to treat immune-based reproductive disorders.
Publisher: Elsevier BV
Date: 02-2013
DOI: 10.1016/J.CYTO.2012.12.002
Abstract: Transforming growth factor beta1 (TGFB1) is a multi-functional cytokine that regulates cell proliferation, apoptosis and immune system responses. In the breast, the mammary epithelium is the primary source of TGFB1 and increased expression is associated with increased breast cancer risk. This study was conducted to investigate the roles of epithelial cell-derived TGFB1 in regulation of epithelial cell activity and macrophage phenotype in the mammary gland. Tgfb1 null mutant and wildtype mammary epithelium was transplanted into contra-lateral sides of the cleared mammary gland of TGFB1 replete scid mice. Transplanted tissue was analysed for markers of proliferation and apoptosis to determine the effect of Tgfb1 null mutation on epithelial cell turnover, and was analysed by immunohistochemistry to investigate the location, abundance and phenotype of macrophages. The number of proliferating and dying ductal epithelial cells, determined by BrdU and TUNEL, was increased by 35% and 3.3-fold respectively in mammary gland transplanted with Tgfb1 null epithelium compared to wildtype epithelium (p<0.05). Abundance of F4/80+ macrophages in between Tgfb1 null epithelial cells compared to wildtype epithelial cells was increased by 50%. The number of iNOS+ and CCR7+ cells in the stroma surrounding Tgfb1 null alveolar epithelium was increased by 78% and 2-fold respectively, and dendriform MHC class II+ cells within ductal epithelium were decreased by 30%. We conclude that epithelial cell-derived TGFB1 in the mammary gland has two functions: (1) regulation of cellular turnover of epithelial cells, and (2) regulation of local macrophage phenotype. These findings shed new light on the ersity of roles of TGFB1 in the mammary gland which are likely to impact on breast cancer risk.
Publisher: Elsevier BV
Date: 10-1995
DOI: 10.1016/0165-0378(95)00941-D
Abstract: To investigate the effect of systemic neutrophil depletion on ovulation rate, rats were synchronised with eCG and hCG, and concurrently were administered neutrophil-specific, cytotoxic RP-3 monoclonal antibody (mAb), or an irrelevant, class-matched mAb. Neutrophils in the peripheral blood and in the thecal-luteal area of corpora lutea were detected by immunohistochemical analysis with the neutrophil-specific mAb MCA149 and were found to be reduced in number by 70% and 38% respectively following RP-3 treatment compared to the control group. Ovulation rate, as assessed by counting the number of oocytes in the ullary region of the oviduct 20 h after hCG administration, was found to be reduced by 27% in the neutrophil-depleted rats. This result provides further evidence that neutrophilic granulocytes play an active role in ovulation in the rat.
Publisher: Elsevier BV
Date: 04-2001
Publisher: Informa UK Limited
Date: 25-10-2017
DOI: 10.1080/14647273.2016.1245447
Abstract: Some potentially modifiable factors adversely affect fertility and pregnancy health. To inform a fertility health promotion programme, this study investigated fertility knowledge and information-seeking behaviour among people of reproductive age. This was a qualitative study involving six focus group discussions with women and men who intended to have children in the future and eight paired interviews with couples who were actively trying to conceive. Participants (n = 74) themselves generally claimed 'low' to 'average' levels of knowledge about fertility. Most of them overestimated women's reproductive lifespan and had limited knowledge about the 'fertile window' of the menstrual cycle. The Internet was a common source of fertility-related information and social media was viewed as a potential effective avenue for dissemination of messages about fertility and how to protect it. Most participants agreed that primary health care providers, such as general practitioners (GPs), are well placed to provide information regarding fertility and pregnancy health. This study identified several gaps in knowledge among people of reproductive age about factors that influence fertility and pregnancy health negatively. Addressing these knowledge gaps in school curricula, primary care and health promotion would assist people to realize their reproductive goals and reduce the risk of infertility and adverse obstetric outcomes.
Publisher: Bioscientifica
Date: 11-2000
Abstract: Interleukin 5 is expressed in type 2 T lymphocytes and has a key role in driving the differentiation, recruitment and activation of eosinophils. Mice with a null mutation in the interleukin 5 gene (IL-5 -/- mice) have altered type 2 immune responses and severely depleted eosinophil populations. In the present study, the effect of interleukin 5 deficiency on the abundant population of eosinophils present in the female reproductive tract was investigated, and the reproductive performance in C57Bl/6 IL-5 -/- mice was measured. Endometrial eosinophils, detected on the basis of their endogenous peroxidase activity, were reduced in number by four-sevenfold during the oestrous cycle and in early pregnancy in IL-5 -/- mice. Eosinophils present in the cervix and decidual tissues at the time of parturition were similarly diminished. The temporal fluctuations in eosinophil recruitment and localization within these tissues were otherwise unchanged, indicating that interleukin 5 is not a necessary chemotactic agent in the female reproductive tract. Oestrous cycles were moderately greater in duration in IL-5 -/- mice (mean +/- SD = 5.6 +/- 1.0 days in IL-5 -/- mice versus 5.0 +/- 0.8 days in IL-5 +/+ mice), owing to an extended period in oestrus (2.7 +/- 0.9 days per cycle in IL-5 -/- mice versus 1.8 +/- 0.7 in IL-5 +/+ mice). The interval between placing females with males and the finding of copulatory plugs was reduced significantly in interleukin 5-deficient mice. Implantation rates and subsequent fetal development were comparable in IL-5 -/- and IL-5 +/+ mice, irrespective of whether pregnancies were sired by syngeneic (C57Bl/6) or allogeneic (CBA or Balb/c) males, apart from a 10% increase in placental size and a 6.5% decrease in placental&ratio fetal ratio seen on day 17 in pregnancies sired by CBA males. Parturition and post-partum uterine repair were not compromised in interleukin 5-deficient mice, as judged by the length of gestation, and the outcomes of pregnancies initiated at post-partum oestrus. The birth weights and growth trajectories of pups were significantly influenced by interleukin 5 status, with small but significant increases in the weights of IL-5 -/- pups, particularly C57Bl/6 and CBA F(1) animals, remaining evident until adulthood. These data are consistent with the view that eosinophils have a role in endometrial tissue remodelling associated with the oestrous cycle, but indicate that the events of pregnancy and parturition proceed quite normally in the absence of maternal and fetal interleukin 5. However, strain-dependent effects of interleukin 5 deficiency on placental growth and function and subsequent weight gain in the newborn indicate that this cytokine may act through the maternal or fetal immune axis to exert subtle influences on reproductive outcome.
Publisher: Oxford University Press (OUP)
Date: 10-2015
DOI: 10.1095/BIOLREPROD.115.128694
Abstract: Maternal interleukin (IL) 10 deficiency elevates susceptibility to fetal loss induced by the model Toll-like receptor agonist lipopolysaccharide, but the mechanisms are not well elucidated. Here, we show that Il10 null mutant (Il10(-/-)) mice exhibit altered local T cell responses in pregnancy, exhibiting pronounced hyperplasia in para-aortic lymph nodes draining the uterus with >6-fold increased CD4(+) and CD8(+) T cells compared with wild-type controls. Among these CD4(+) cells, Foxp3(+) T regulatory (Treg) cells were substantially enriched, with 11-fold higher numbers at Day 9.5 postcoitum. Lymph node hypertrophy in Il10(-/-) mice was associated with more activated phenotypes in dendritic cells and macrophages, with elevated expression of MHCII, scavenger receptor, and CD80. Affymetrix microarray revealed an altered transcriptional profile in Treg cells from pregnant Il10(-/-) mice, with elevated expression of Ctse (cathepsin E), Il1r1, Il12rb2, and Ifng. In vitro, Il10(-/-) Treg cells showed reduced steady-state Foxp3 expression, and polyclonal stimulation caused greater loss of Foxp3 and reduced capacity to suppress IL17 in CD4(+)Foxp3(-) T cells. We conclude that despite a substantially expanded Treg cell pool, the diminished stability of Treg cells, increased numbers of effector T cells, and altered phenotypes in dendritic cells and macrophages in pregnancy all potentially confer vulnerability to inflammation-induced fetal loss in Il10(-/-) mice. These findings suggest that IL10 has a pivotal role in facilitating robust immune protection of the fetus from inflammatory challenge and that IL10 deficiency could contribute to human gestational disorders in which altered T cell responses are implicated.
Publisher: The Endocrine Society
Date: 08-2007
DOI: 10.1210/EN.2006-1759
Abstract: TGFbeta1 is a multifunctional cytokine implicated in gonad and secondary sex organ development, steroidogenesis, and spermatogenesis. To determine the physiological requirement for TGFbeta1 in male reproduction, Tgfb1 null mutant mice on a Prkdc(scid) immunodeficient background were studied. TGFbeta1-deficient males did not deposit sperm or induce pseudopregnancy in females, despite an intact reproductive tract with morphologically normal penis, seminal vesicles, and testes. Serum and intratesticular testosterone and serum androstenedione were severely diminished in TGFbeta1-deficient males. Testosterone deficiency was secondary to disrupted pituitary gonadotropin secretion because serum LH and to a lesser extent serum FSH were reduced, and exogenous LH replacement with human chorionic gonadotropin (hCG) induced serum testosterone to control levels. In the majority of TGFbeta1-deficient males, spermatogenesis was normal and sperm were developmentally competent as assessed by in vitro fertilization. Analysis of sexual behavior revealed that although TGFbeta1 null males showed avid interest in females and engaged in mounting activity, intromission was infrequent and brief, and ejaculation was not attained. Administration of testosterone to adult males, even after neonatal androgenization, was ineffective in restoring sexual function however, erectile reflexes and ejaculation could be induced by electrical stimulation. These studies demonstrate the profound effect of genetic deficiency in TGFbeta1 on male fertility, implicating this cytokine in essential roles in the hypothalamic-pituitary-gonadal axis and in testosterone-independent regulation of mating competence.
Publisher: Springer Science and Business Media LLC
Date: 14-05-2021
DOI: 10.1038/S42003-021-02038-9
Abstract: Seminal fluid factors modulate the female immune response at conception to facilitate embryo implantation and reproductive success. Whether sperm affect this response has not been clear. We evaluated global gene expression by microarray in the mouse uterus after mating with intact or vasectomized males. Intact males induced greater changes in gene transcription, prominently affecting pro-inflammatory cytokine and immune regulatory genes, with TLR4 signaling identified as a top-ranked upstream driver. Recruitment of neutrophils and expansion of peripheral regulatory T cells were elevated by seminal fluid of intact males. In vitro, epididymal sperm induced IL6, CXCL2, and CSF3 in uterine epithelial cells of wild-type, but not Tlr4 null females. Collectively these experiments show that sperm assist in promoting female immune tolerance by eliciting uterine cytokine expression through TLR4-dependent signaling. The findings indicate a biological role for sperm beyond oocyte fertilization, in modulating immune mechanisms involved in female control of reproductive investment.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 06-12-2019
Abstract: A novel T cell–based ZIKV vaccine, encoding NS1 protein, confers protection against systemic infection.
Publisher: Elsevier BV
Date: 12-2010
DOI: 10.1016/J.JRI.2010.05.007
Abstract: Studies in mice demonstrate that the maternal T cell repertoire is aware of paternal antigens during pregnancy, but in healthy pregnancy reactive T cells do not mediate anti-fetal immunity. Mice expressing transgenic T cell receptors (TCRs) specific for paternal and conceptus antigens are powerful tools for elucidating the events surrounding paternal antigen presentation to the maternal T cell repertoire, the nature of the ensuing T cell response and the factors that skew the response towards immune tolerance to allow survival and development of the conceptus. While results from different transgenic TCR models are not always consistent, there is now sufficient data to allow a consensus interpretation that maternal antigen presenting cells present initially seminal fluid antigens and later placenta-derived antigens to both the CD4+ and CD8+ T cell repertoire. T cell proliferation is generally followed by entry into a state of anergy demonstrated by decreased cytokine production and hyporesponsiveness upon restimulation. Some models also demonstrate downregulation of the TCR and co-stimulatory molecules, clonal deletion of paternal antigen-reactive T cells, or alternatively T cell ignorance of paternal antigens. This review will summarise the range of transgenic TCR studies that have shed light on the events surrounding paternal antigen presentation and the various T cell responses to insemination and pregnancy. The benefits, limitations and caveats of these models, and their impact upon data interpretation, are discussed.
Publisher: Elsevier BV
Date: 08-2004
Publisher: The Endocrine Society
Date: 02-2015
DOI: 10.1210/ER.2014-1079
Publisher: Springer Science and Business Media LLC
Date: 15-04-2020
DOI: 10.1038/S41598-020-63705-1
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher: Wiley
Date: 27-06-2020
DOI: 10.1038/ICB.2017.41
Abstract: Central to pregnancy success is a state of T cell tolerance to paternal antigens, which is initiated at conception. The role and regulation of specific phenotypes of CD8
Publisher: The Endocrine Society
Date: 02-2009
DOI: 10.1210/ME.2008-0387
Publisher: Oxford University Press (OUP)
Date: 03-2007
DOI: 10.2527/JAS.2006-578
Abstract: Seminal fluid contains potent signaling agents that influence female reproductive physiology to improve the chances of conception and pregnancy success. Cytokines and prostaglandins synthesized in the male accessory glands are transferred to the female at insemination, where they bind to receptors on target cells in the cervix and uterus, activating changes in gene expression that lead to modifications in structure and function of the female tissues. The consequences are increased sperm survival and fertilization rates, conditioning of the female immune response to tolerate semen and the conceptus, and molecular and cellular changes in the endometrium that facilitate embryo development and implantation. Male-female tract signaling occurs in rodents, livestock animals, and all other mammals examined thus far, including humans. In mice, the key signaling moieties in seminal plasma are identified as members of the transforming growth factor-beta family. Recent studies indicate a similar signaling function for boar factors in the pig, whereby the sperm and plasma fractions of seminal fluid appear to synergize in activating an inflammatory response and downstream changes in the female tract after insemination. Seminal plasma elicits endometrial changes, with induction of proinflammatory cytokines and cyclooxygenase-2, causing recruitment of macrophages and dendritic cells. Sperm contribute by interacting with seminal plasma factors to modulate neutrophil influx into the luminal cavity. The cascade of changes in local leukocyte populations and cytokine synthesis persists throughout the preimplantation period. Exposure to seminal fluid alters the dynamics of preimplantation embryo development, with an increase in the number of fertilized oocytes attaining the viable blastocyst stage. There is also evidence that seminal factors influence the timing of ovulation, corpus luteum development, and progesterone synthesis. Insight into the molecular basis of seminal fluid signaling in the female reproductive tract may inform new interventions and management practices to ensure maximal fertility and reduce embryo mortality in pigs and, potentially, other livestock species.
Publisher: Springer Science and Business Media LLC
Date: 21-05-2005
DOI: 10.1007/S00441-005-1127-3
Abstract: In mammals, insemination results in the transmission of seminal factors that act, in the female reproductive tract, to promote sperm survival, to "condition" the female immune response to tolerate the conceptus and to organise molecular and cellular changes in the endometrium to facilitate embryo development and implantation. These events are initiated when signalling agents, including transforming growth factor-beta and other cytokines and prostaglandins secreted by seminal vesicle and prostate glands, interact with epithelial cells in the cervix and uterus to activate cytokine synthesis and to induce cellular and molecular changes resembling a classical inflammatory cascade. The consequences are the recruitment and activation of macrophages, granulocytes and dendritic cells, which have immune-regulatory and tissue-remodelling roles that culminate in improved endometrial receptivity to the implanting embryo. Cytokines elicited by seminal activation have embryotrophic properties and also contribute directly to the optimal development of the early embryo. This review summarises our current understanding of the physiology of responses to seminal plasma in the female reproductive tract and considers the evolutionary significance of seminal plasma in influencing female tissues to promote the success of pregnancy.
Publisher: CSIRO Publishing
Date: 1990
DOI: 10.1071/RD9900359
Abstract: The activity of GM-CSF during early pregnancy in the murine uterine lumen in vivo and in media conditioned by uterine cells in vitro has been assessed. GM-CSF was detected in uterine luminal fluid recovered by lavage on the morning after syngeneic mating (median level 5.7 CFUc U/uterus) and following mating with vasectomized (5.1 U/uterus) or allogeneic males (4.4 U/uterus), with significantly lesser (P less than 0.05) amounts recovered from the uteri of superovulated, mated mice. By contrast, GM-CSF was only detectable (greater than 0.5 U/uterus) in the luminal fluid of three of 22 unmated oestrous mice examined. No activity was detected in secretions from male accessory glands including seminal vesicle, epididymis, prostate and coagulating gland (less than 0.5 U/gland). GM-CSF was found at higher levels in supernatants from cell monolayers prepared by tryptic digest of the uteri of Day 1 mated mice than those from unmated oestrous mice (P less than 0.05). Little GM-CSF was detected in supernatants from ovariectomized mice. An alpha-GM-CSF polyvalent antibody neutralized the FD5/12 bioassay response confirming the identity of the lymphokine. The interleukins IL-2 and IL-3 were not detected in uterine luminal fluid nor in media conditioned by cell monolayers. We postulate that elevated uterine GM-CSF activity after mating is elicited by a non-sperm associated, non-MHC component of the ejaculate and synthesized by a hormone-responsive endometrial cell population. This cytokine may have an embryotrophic role or contribute to priming of the uterus for implantation.
Publisher: Elsevier BV
Date: 03-2012
DOI: 10.1016/J.AJPATH.2011.11.013
Abstract: Transforming growth factor-β1 (TGFB1) is a multifunctional cytokine that is abundant in both endometriotic lesions and the peritoneal fluid in women with endometriosis. However, the role of TGFB1 in the development of endometriosis is as yet undefined. In the present study, we investigated the physiologic function of TGFB1 in endometriotic lesion development, using Tgfb1-null mutant mice on a background of severe combined immunodeficiency. Xenotransplantation of human eutopic endometrial tissue resulted in development of endometriosis-like lesions in 63% of ovariectomized estrogen-supplemented Tgfb1-null mutant mice and in 68% of wild-type control mice. Median lesion weight was reduced by 11-fold in Tgfb1-null mice compared with wild-type control mice, and the fraction of glandular epithelium in lesions from Tgfb1-null mice was reduced by 32% compared with that in control mice. In lesions from Tgfb1-null mice, the relative abundance of both macrophages and α-smooth muscle actin-positive myofibroblasts was reduced by 66% and 47%, respectively. Deficiency of TGFB1 neither altered the percentage of proliferating cells in the epithelial or stromal compartments of the lesions nor affected blood vessel density or vessel size. Observation of this study indicates that host-derived TGFB1 deficiency suppresses endometriotic lesion development and provides proof of principle that targeting TGFB1 signaling pathways in cells that support the survival of ectopic endometrium may be an effective therapeutic approach in women with endometriosis.
Publisher: The Company of Biologists
Date: 15-12-2010
DOI: 10.1242/DEV.059261
Abstract: Each ovarian cycle, the mammary gland epithelium rotates through a sequence of hormonally regulated cell proliferation, differentiation and apoptosis. These studies investigate the role of macrophages in this cellular turnover. Macrophage populations and their spatial distribution were found to fluctuate across the cycle. The number of macrophages was highest at diestrus, and the greatest number of macrophages in direct contact with epithelial cells occurred at proestrus. The physiological necessity of macrophages in mammary gland morphogenesis during the estrous cycle was demonstrated in Cd11b-Dtr transgenic mice. Ovariectomised mice were treated with estradiol and progesterone to stimulate alveolar development, and with the progesterone receptor antagonist mifepristone to induce regression of the newly formed alveolar buds. Macrophage depletion during alveolar development resulted in a reduction in both ductal epithelial cell proliferation and the number of alveolar buds. Macrophage depletion during alveolar regression resulted in an increased number of branch points and an accumulation of TUNEL-positive cells. These studies show that macrophages have two roles in the cellular turnover of epithelial cells in the cycling mammary gland following ovulation, they promote the development of alveolar buds in preparation for possible pregnancy, and they remodel the tissue back to its basic architecture in preparation for a new estrous cycle.
Publisher: Proceedings of the National Academy of Sciences
Date: 27-01-2014
Abstract: Events at conception shape the future growth and health of offspring, to impact life course potential and disease susceptibility. The environment and experiences of both parents contribute to programming offspring phenotype through epigenetic modifications imparted before embryo implantation. How the father transmits this information remains elusive. Possible pathways include the sperm genome and epigenome, postejaculatory effects of seminal fluid on sperm, and indirect actions of seminal fluid on various female factors regulating embryo development. In this study, we provide evidence that seminal fluid acts to influence both sperm integrity and the balance of embryotrophic and embryotoxic signals in the female reproductive tract, in turn affecting embryo development and programming of future adiposity and metabolic phenotype in male offspring.
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.MCE.2015.09.022
Abstract: Seminal fluid induces pro-inflammatory cytokines and elicits an inflammation-like response in the cervix. Here, Affymetrix microarray and qPCR was utilised to identify activin A (INHBA) and its inhibitor follistatin (FST) amongst the cytokines induced by seminal plasma in Ect1 ectocervical epithelial cells, and a similar response was confirmed in primary ectocervical epithelial cells. TGFB is abundant in seminal plasma and all three TGFB isoforms induced INHBA in Ect1 and primary cells, and neutralisation of TGFB in seminal plasma suppressed the INHBA response. Bacterial lipopolysaccharide in seminal plasma also elicited INHBA, but potently suppressed FST production. There was moderate reciprocal inhibition between FST and INHBA, and cross-attenuating effects were seen. These data identify TGFB and potentially LPS as factors mediating seminal plasma-induced INHBA synthesis in cervical cells. INHBA and FST induced by seminal fluid in cervical tissues may thus contribute to regulation of the post-coital response in women.
Publisher: CSIRO Publishing
Date: 2011
DOI: 10.1071/RD11001
Abstract: Bioactive factors in seminal plasma induce cellular and molecular changes in the female reproductive tract after coitus. An active constituent of seminal plasma in mice and humans is the potent immune-modulating cytokine transforming growth factor-β (TGFβ). To investigate whether TGFβ is present in boar seminal plasma, TGFβ1 and TGFβ2 were measured by immunoassay. High levels of TGFβ1 and TGFβ2 were detected in 100% of seminal fluid s les from 73 boars. Both were predominantly in the active, not latent form. Interferon-γ (IFNγ) and lipopolysaccharide (LPS), agents that interact with TGFβ signalling, were detectable in 5% and 100% of s les, respectively. TGFβ1 and TGFβ2 concentrations varied widely between boars, but correlated with each other and with sperm density, and remained relatively constant within in idual boars over a 6-month period. Frequent semen collection substantially diminished the concentration of both TGFβ isoforms. Using retrospective breeding data for 44 boars, no correlation between TGFβ content and boar reproductive performance by artificial insemination (AI) with diluted semen was found. It is concluded that TGFβ is abundant in boar seminal plasma, leading to the speculation that, in pigs, TGFβ may be a male–female signalling agent involved in immune changes in the female reproductive tract elicited by seminal fluid.
Publisher: Frontiers Media SA
Date: 10-05-2016
Publisher: Wiley
Date: 08-2016
DOI: 10.1002/MRD.22680
Abstract: The preimplantation embryo is extraordinarily sensitive to environmental signals and events such that perturbations can alter embryo metabolism and program an altered developmental trajectory, ultimately affecting the phenotype of the adult in idual indeed, the physical environment associated with in vitro embryo culture can attenuate development. Defining the underlying metabolic changes and mechanisms, however, has been limited by the imaging technology used to evaluate metabolites and structural features in the embryo. Here, we assessed the impact of in vitro fertilization and culture on mouse embryos using three metabolic markers: peroxyfluor 1 (a reporter of hydrogen peroxide), monochlorobimane (a reporter of glutathione), and Mitotracker Deep Red (a marker of mitochondria). We also evaluated the distribution pattern of histone 2AX gamma (γH2AX) in the nuclei of 2- and 8-cell embryos and blastocysts to investigate the degree of DNA damage caused by in vitro embryo culture. In vitro-fertilized embryos, in vivo-developed embryos, and in vivo-fertilized embryos recovered and cultured in vitro were compared at the 2-, 8-cell, and blastocyst stages. In addition to assessments based on fluorescence intensity, textural analysis using Gray Level Co-occurrence Matrix (GLCM), a statistical approach that assesses texture within an image, was used to evaluate peroxyfluor 1, monochlorobimane, and Mitotracker Deep Red staining in an effort to develop a robust metric of embryo quality. Our data provide strong evidence of modified metabolic parameters identifiable as altered fluorescence texture in embryos developed in vitro. Thus, texture-analysis approach may provide a means of gaining additional insight into embryo programming beyond conventional measurements of staining intensity for metabolic markers. Mol. Reprod. Dev. 83: 701-713, 2016 © 2016 Wiley Periodicals, Inc.
Publisher: Oxford University Press (OUP)
Date: 13-04-2006
Abstract: A receptive endometrial environment requires adequate immunological tolerance to protect the implanting embryo from maternal immune rejection. Studies in mice implicate CD4+CD25+ T-regulatory (Treg) cells as essential mediators of immune tolerance in pregnancy. The aim of this study was to evaluate the link between Treg cells and fertility in women. Expression of Foxp3, a master regulator of Treg cell differentiation, was quantified in endometrial tissue from women experiencing primary unexplained infertility and normal fertile women. Endometrial biopsies were collected during the mid-secretory phase of the menstrual cycle from women meeting rigorously defined criteria for unexplained infertility after experiencing repeated failed cycles of IVF treatment (infertile, n = 10), or women classified as proven fertile (control, n = 12). Expression of Foxp3 mRNA was reduced approximately two-fold in the tissue of infertile women. In contrast, mRNAs encoding T cell transcription factors T-bet and GATA3, associated with differentiation of Th1 and Th2 CD4+ T cells respectively, were unchanged. Treg cell differentiation is controlled by TGFbeta, but the relative abundance in endometrial tissue of TGFbeta1, TGFbeta2, TGFbeta3 mRNAs was not changed in infertile women. Cytokines influencing Th1 and Th2 cell differentiation, including IFNgamma, IL-2, IL-4, IL-5, IL-10 and IL-12p40, as well as dendritic cell-regulating cytokines IL-1alpha, IL-1beta, IL-6, LIF, GM-CSF and TNFalpha were also expressed similarly regardless of fertility status. The finding of reduced endometrial Foxp3 implicates impaired differentiation of uterine T cells into the Treg phenotype as a key determinant of fertility in women. The factors underpinning this aberration in the immune response remain to be identified.
Publisher: BMJ
Date: 08-2018
DOI: 10.1136/BMJOPEN-2018-021619
Abstract: To establish pregnancy, the maternal immune system must adapt to tolerate the semiallogenic fetus. Less than optimal adaptation of the maternal immune system during (early) pregnancy is implicated in several complications of pregnancy. The development of effective immune modulation interventions as preventive or therapeutic strategies for pregnancy complications holds promise. Several studies sought to evaluate the safety and effectiveness of various approaches. However, a limitation is the high variability in clinical and immune outcomes that are reported. We, therefore, aim to develop a core outcome set for application to studies of immune modulation in pregnancy (COSIMPREG). We will use a stepwise approach to develop a COSIMPREG. First, we will perform a systematic review to identify reported outcomes. For this review, Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines will be followed. Second, we will use the Delphi method to develop a preliminary COSIMPREG. In three rounds, the outcomes of the systematic review will be scored. A panel comprising experts from relevant disciplines and erse geographical locations will be assembled until a sufficient quality of the panel is reached. We will use predefined decision rules for outcomes. After each round outcomes, including scores, will be returned to the panel for further refinement. The outcomes not excluded after the third round will be taken to a consensus meeting. In this meeting, experts from all relevant disciplines will discuss and finalise the COSIMPREG. For this study ethical approval is not required. The systematic review will be published in an appropriate open access reproductive immunology journal. Once the COSIMPREG is finalised, it will be published in an open access reproductive immunology journal, and disseminated at appropriate international meetings, as well as through relevant research and scientific societies. Experts involved in the Delphi study will be asked to give informed consent.
Publisher: Elsevier BV
Date: 10-2008
DOI: 10.1016/J.JRI.2008.04.002
Abstract: A role for the pro-inflammatory cytokines interleukin (IL)-1beta, IL-6, IL-8 and tumor necrosis factor alpha (TNF-alpha) is evident in term and preterm delivery, and this is independent of the presence of infection. All uterine tissues progress through a staged transformation near the end of pregnancy that leads from relative uterine quiescence and maintenance of pregnancy to the activation of the uterus that prepares it for the work of labour and production of stimulatory molecules that trigger the onset of labour and delivery. The uterus is activated by pro-inflammatory cytokines through stimulation of the expression and production of uterine activation proteins (UAPs). One of these actions is the stimulation of prostaglandin (PG) synthesis. Particularly important for labour is PGF(2alpha) and its receptor, PTGFR. In addition, pro-inflammatory cytokines are able to increase the synthesis of matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF) and the progesterone receptor C isoform, which leads to decreased tissue progesterone responsiveness. Some of these effects are replicated by PGF(2alpha), suggesting that it may act via its receptor to lify the direct actions of cytokines. In turn, VEGF may enhance leukocyte recruitment to the uterus, and MMP-9 may promote activation of inactive pro-form cytokines. Pro-inflammatory cytokines also decrease the activity of 11beta-hydroxysteroid dehydrogenase, which likely increases intrauterine cortisol concentrations. In turn, cortisol may drive PG synthesis. Together these feed-forward mechanisms activate the uterus, trigger the production of uterine contractile stimulants and lead to labour and delivery.
Publisher: Elsevier BV
Date: 08-1997
Publisher: Elsevier BV
Date: 05-2010
DOI: 10.1016/J.JRI.2010.01.008
Abstract: Medawar's hypotheses for explaining maternal immune tolerance of the semi-allogeneic fetus are now proven incorrect or insufficient. The mother's immune response is not passive, suppressed, indolent or physically constrained in pregnancy. Instead, her immune system is centrally engaged with all steps of the reproductive process from conception to embryo implantation and placental development. Emerging studies show that immune cells are positioned and equipped to sense antigens and other signals originating in seminal fluid, the embryo and placental trophoblast. The immune response appears competent to utilise this information to discriminate the reproductive fitness and compatibility of the male partner and the integrity and developmental competence of the conceptus tissue. Since the immune response is modulated by the in idual's infectious, inflammatory, stress, nutritional and metabolic status, immune influence on progression or disruption of pregnancy may be further influenced by environmental stressors and resource availability. This opinion paper advances the view that the immune system operates in pregnancy to integrate these signals and to exert executive quality control to either accommodate or reject the conceptus. It is argued that 'immune-mediated quality control' would facilitate optimal female reproductive investment and maximise offspring fitness, and thereby explain the evolutionary advantage of maternal immune awareness of the conceptus tissue.
Publisher: Wiley
Date: 19-02-2009
DOI: 10.2164/JANDROL.108.006569
Abstract: The cytokine transforming growth factor beta1 (TGFB1) is implicated in male sexual function. Previous behavioral studies show that Tgfb1 null mutant mice mount and display limited intromission behavior with receptive females but are unable to complete successful copulation. The studies presented here explore the physiologic basis for sexual dysfunction in Tgfb1 null mutant males. Scanning electron microscopy revealed that the surface of the penis in Tgfb1 null mutant males was abnormally coated in superficial keratinized epithelial cells. There was a significant reduction in protrusion of penile spines through the superficial tissue in Tgfb1 null mutant mice in some mice, the spines were almost completely embedded. Histologic analysis revealed reduced skin thickness in the penis of Tgfb1 null mutant males. Nerve fibers, endothelial cells, smooth muscle actin, macrophages, and neuronal and inducible nitric oxide synthase were present in similar abundance and location in Tgfb1 null mutant mice compared with wild-type controls however, an increase in collagen I deposition was detected. Behavioral studies revealed that Tgfb1 null mutant males undergo spontaneous noncontact erections, albeit at a reduced rate compared with control mice, and engage in less frequent genital grooming activity. These studies suggest that Tgfb1 null mutation may adversely influence copulatory behavior through effects on both altered structural integrity of the penile skin and impaired tissue compliance leading to erectile dysfunction.
Publisher: MDPI AG
Date: 21-01-2021
Abstract: High amylose wheat (HAW) contains more resistant starch than standard amylose wheat (SAW) and may have beneficial effects on gastrointestinal health. However, it is currently unclear whether these effects differ according to the level of HAW included in the diet or between males and females. Male and female C57BL/6 mice (n = 8/group/sex) were fed SAW65 (65% SAW control), HAW35 (35% HAW), HAW50 (50% HAW) or HAW65 (65% HAW) diet for eight weeks. Female but not male, mice consuming any amount of HAW exhibited accelerated gastric emptying compared to SAW65 group. In both sexes, relative colon weights were higher in the HAW65 group compared to SAW65 group and in females, relative weights of the small intestine and cecum were also higher in the HAW65 group. In females only, colonic expression of Pyy and Ocln mRNAs were higher in the HAW65 group compared to HAW35 and HAW50 groups. In both sexes, mice consuming higher amounts of HAW (HAW50 or HAW65) had increased fecal bacterial load and relative abundance of Bacteroidetes phylum and reduced relative abundance of Firmicutes compared to SAW65 group. These data are consistent with a beneficial impact of HAW on gastrointestinal health and indicate dose-dependent and sex-specific effects of HAW consumption.
Publisher: Oxford University Press (OUP)
Date: 03-11-2011
Abstract: The epithelial cell surface of the endometrium undergoes substantial biochemical changes to allow embryo attachment and implantation in early pregnancy. We hypothesized that tissue macrophages influence these events to promote uterine receptivity. To investigate the role of macrophages in regulating epithelial cell expression of genes linked to glycan-mediated embryo adhesion, Ishikawa, RL95-2 and HEC1A endometrial epithelial cells were cultured alone or with unactivated or lipopolysaccharide-activated monocytic U937 cells, separated using transwell inserts. Expression of mRNAs encoding two α1,2-fucosyltransferases (FUT1, FUT2) was increased in all three epithelial cell lines following co-culture with U937 cells, and was associated with increased fucosylation of cell surface glycoproteins detected using lectins from Ulex europaeus (UEA-1) and Dolichos biflorus (DBA). FUT1 induction by U937 cells also occurred in primary endometrial epithelial cells collected in luteal but not proliferative phase. Activation of the interleukin-6 (IL6)/leukemia inhibitory factor (LIF) cytokine signaling pathway with phosphorylation of STAT3 and elevated SOCS3 mRNA expression was evident in epithelial cells stimulated by U937 co-culture. Several recombinant macrophage-secreted cytokines exerted stimulatory or inhibitory effects on FUT1 and FUT2 mRNA expression, and the macrophage-derived cytokine LIF partially replicated the effects of U937 cells on both FUT1 and FUT2 expression and UEA-1 and DBA lectin reactivity in Ishikawa cells. These results suggest that macrophage-derived factors including LIF might facilitate development of an implantation-receptive endometrium by regulating surface glycan structures in epithelial cells. Abnormal phenotypes or altered abundance of uterine macrophages could contribute to the pathophysiology of primary unexplained infertility in women.
Publisher: Elsevier BV
Date: 06-2007
DOI: 10.1016/J.CYTOGFR.2007.04.008
Abstract: The reproductive tissues undergo profound structural changes and major immune adaptation to accommodate pregnancy. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is one of an array of cytokines with pivotal roles in embryo implantation and subsequent development. Several cell lineages in the reproductive tract and gestational tissues synthesise GM-CSF under direction by ovarian steroid hormones and signalling agents originating in male seminal fluid and the conceptus. The pre-implantation embryo, invading placental trophoblast cells and the abundant populations of leukocytes controlling maternal immune tolerance are all subject to GM-CSF regulation. GM-CSF deficiency in pregnancy adversely impacts fetal and placental development, as well as progeny viability and growth after birth, highlighting this cytokine as a central maternal determinant of pregnancy outcome with clinical relevance in human fertility.
Publisher: Elsevier BV
Date: 05-2013
DOI: 10.1016/J.FERTNSTERT.2012.12.043
Abstract: To evaluate the effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) in embryo culture medium on ongoing implantation rate (OIR). Multicenter, randomized, placebo-controlled, double-blinded prospective design. Fourteen Scandinavian fertility clinics. A total of 1,332 women with indication for in vitro fertilization or intracytoplasmic sperm injection 1,149 received embryo transfer (GM-CSF: n = 564 control: n = 585). Oocytes were fertilized, and embryos cultured and transferred in control medium or test medium containing 2 ng/mL GM-CSF. OIR at gestational week 7, with follow-up at week 12 and birth. At week 7, OIRs were 23.5% (GM-CSF), and 20.0% (control) (odds ratio [OR] 1.26, 95% confidence interval [CI] 0.91-1.75). At week 12, OIRs were 23.0% (GM-CSF) and 18.7% (control) (OR 1.35, 95% CI 1.06-1.72), and live birth rates were 28.9% and 24.1%, respectively (OR 1.35, 95% CI 1.03-1.78). The effect of GM-CSF was influenced by the human serum albumin concentration in the medium. Birth weight and abnormality incidence were similar in both groups. Exploratory analyses showed that GM-CSF increased OIR in women with previous miscarriage, especially in women with more than one miscarriage. Addition of GM-CSF to embryo culture medium elicits a significant increase in survival of transferred embryos to week 12 and live birth. Our results are consistent with a protective effect of GM-CSF on culture-induced embryo stress. GM-CSF may be particularly efficacious in women with previous miscarriage. NCT00565747.
Publisher: Oxford University Press (OUP)
Date: 2004
Publisher: American Society for Clinical Investigation
Date: 08-10-2021
Publisher: The American Association of Immunologists
Date: 03-2017
Abstract: Preterm birth (PTB) is commonly accompanied by in utero fetal inflammation, and existing tocolytic drugs do not target fetal inflammatory injury. Of the candidate proinflammatory mediators, IL-1 appears central and is sufficient to trigger fetal loss. Therefore, we elucidated the effects of antenatal IL-1 exposure on postnatal development and investigated two IL-1 receptor antagonists, the competitive inhibitor anakinra (Kineret) and a potent noncompetitive inhibitor 101.10, for efficacy in blocking IL-1 actions. Antenatal exposure to IL-1β induced Tnfa, Il6, Ccl2, Pghs2, and Mpges1 expression in placenta and fetal membranes, and it elevated amniotic fluid IL-1β, IL-6, IL-8, and PGF2α, resulting in PTB and marked neonatal mortality. Surviving neonates had increased Il1b, Il6, Il8, Il10, Pghs2, Tnfa, and Crp expression in WBCs, elevated plasma levels of IL-1β, IL-6, and IL-8, increased IL-1β, IL-6, and IL-8 in fetal lung, intestine, and brain, and morphological abnormalities: e.g., disrupted lung alveolarization, atrophy of intestinal villus and colon-resident lymphoid follicle, and degeneration and atrophy of brain microvasculature with visual evoked potential anomalies. Late gestation treatment with 101.10 abolished these adverse outcomes, whereas Kineret exerted only modest effects and no benefit for gestation length, neonatal mortality, or placental inflammation. In a LPS-induced model of infection-associated PTB, 101.10 prevented PTB, neonatal mortality, and fetal brain inflammation. There was no substantive deviation in postnatal growth trajectory or adult body morphometry after antenatal 101.10 treatment. The results implicate IL-1 as an important driver of neonatal morbidity in PTB and identify 101.10 as a safe and effective candidate therapeutic.
Publisher: Oxford University Press (OUP)
Date: 02-1999
DOI: 10.1095/BIOLREPROD60.2.251
Abstract: Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been identified as a potentially important mediator of intercellular communication in the female reproductive tract, with principal target cells being the large populations of myeloid leukocytes in the cycling and pregnant uterus, the preimplantation embryo, and trophoblast cells of the developing placenta. To determine the physiological significance of this cytokine in reproduction, the fertility of genetically GM-CSF-deficient (GM-/-) mice was examined. Implantation rates were normal in GM-/- mice, and viable pups were produced. However, the mean litter sizes of GM-/- x GM-/- breeding pairs were 25% smaller at weaning than those of GM+/- x GM+/- pairs, due to fetal death late in gestation and early in postnatal life, with a disproportionate loss of male pups. On Day 17 of pregnancy, the mean number of resorbing and malformed fetuses was twice as high in pregnant GM-/- females (21%, vs. 11% in GM+/- females) the mean fetal weight and the mean fetal:placental ratio in surviving conceptuses were diminished by 7% and 6%, respectively and the number of very small fetuses (< 500 mg) was 9-times as high (23% vs. 2.5%). Mortality during the first 3 wk of life was 4.5-times as high in pups born to GM-/- mothers (9%, vs. 2% in GM+/- females), and diminished size persisted in GM-/- pups, particularly males, into adulthood. The detrimental effect of maternal GM-CSF deficiency was less apparent when GM-/- females were mated with GM+/+ males litter sizes at birth and at weaning were not significantly smaller than in GM+/- matings, and fetal weights and fetal:placental ratios were also comparable. When polymerase chain reaction was used to genotype embryonic tissue in heterozygote matings, GM-/- fetuses from GM-/- females were found to be smaller than their GM+/- littermates and smaller than GM-/- fetuses gestated in GM+/- females. The size and distribution of uterine granulocyte and macrophage populations were normal during the estrous cycle, during early pregnancy, and in midgestation. Analysis of placental structure revealed that the ratio of labyrinthine to spongiotrophoblast areas was reduced by approximately 28% in GM-/- placentae, and the proportion of vacuolated trophoblast "glycogen cells" in the spongiotrophoblast layer was diminished. Compromised placental function as a result of subtle developmental aberrations may therefore partially account for embryonic growth retardation in GM-CSF-deficient mice. Collectively, these studies show that fetal growth and viability are jeopardized in the absence of maternal GM-CSF. The detrimental effects are most clearly evident when the conceptus is also GM-CSF deficient, suggesting that GM-CSF of either maternal or fetal origin is required for optimal growth and survival of the fetus in mice.
Publisher: Elsevier BV
Date: 03-2019
DOI: 10.1016/J.MEHY.2019.01.019
Abstract: Polycystic ovary syndrome (PCOS) affects around 10% of women of reproductive age and is most common in developed countries. The aetiology of PCOS is not completely understood. Current evidence suggests that the syndrome results from a genetic predisposition interacting with developmental events during fetal or perinatal life that together increase susceptibility in some in iduals. This implies that environmental factors influence the initiation of PCOS in the fetus or infant, either directly or via the mother. PCOS is often considered to be an ancient disorder but there is no direct proof of this in the medical or historic record. One of the cardinal features, polycystic ovaries, was first described only in the early 1900s, despite reports of many thousands of autopsies recorded earlier. This conundrum could be explained by postulating that polycystic ovaries were rare before the 1900s and have become more common over the last 100 years. The hypothesis that PCOS is a syndrome of the 20th Century would eliminate the need to explain the paradox of why there exists a genetic predisposition to subfertility syndrome.
Publisher: American Society for Microbiology
Date: 04-2011
DOI: 10.1128/JVI.02000-10
Abstract: Fowlpox virus (FWPV) is a double-stranded DNA virus long used as a live-attenuated vaccine against poultry diseases, but more recent interest has focused on its use as a mammalian vaccine vector. Here, in a mouse model system using FWPV encoding the nominal target antigen chicken ovalbumin (OVA) (FWPV OVA ), we describe for the first time some of the fundamental processes by which FWPV engages both the innate and adaptive immune systems. We show that Toll-like receptor 7 (TLR7) and TLR9 are important for type I interferon secretion by dendritic cells, while TLR9 is solely required for proinflammatory cytokine secretion. Despite this functional role for TLR7 and TLR9 in vitro , only the adapter protein myeloid differentiation primary response gene 88 (MyD88) was shown to be essential for the formation of adaptive immunity to FWPV OVA in vivo . The dependence on MyD88 was confined only to the T-cell compartment and was not related to its contribution to TLR signaling, dendritic cell maturation, or the capture and presentation of FWPV-derived OVA antigen. We demonstrate that this is not by means of mediating T-cell-dependent interleukin-1 (IL-1) signaling, but rather, we suggest that MyD88 functions to support T-cell-specific IL-18 receptor signaling, which in turn is essential for the formation of adaptive immunity to FWPV-encoded OVA.
Publisher: Elsevier BV
Date: 05-2020
Publisher: MDPI AG
Date: 13-01-2016
DOI: 10.3390/NU8010035
Publisher: The Endocrine Society
Date: 25-06-2021
Abstract: Paternal experiences and exposures before conception can influence fetal development and offspring phenotype. The composition of seminal plasma contributes to paternal programming effects through modulating the female reproductive tract immune response after mating. To investigate whether paternal obesity affects seminal plasma immune-regulatory activity, C57Bl/6 male mice were fed an obesogenic high-fat diet (HFD) or control diet (CD) for 14 weeks. Although HFD consumption caused only minor changes to parameters of sperm quality, the volume of seminal vesicle fluid secretions was increased by 65%, and the concentrations and total content of immune-regulatory TGF-β isoforms were decreased by 75% to 80% and 43% to 55%, respectively. Mating with BALB/c females revealed differences in the strength and properties of the postmating immune response elicited. Transcriptional analysis showed & inflammatory genes were similarly regulated in the uterine endometrium by mating independently of paternal diet, and 13 were dysregulated by HFD-fed compared with CD-fed males. Seminal vesicle fluid factors reduced in HFD-fed males, including TGF-β1, IL-10, and TNF, were among the predicted upstream regulators of differentially regulated genes. Additionally, the T-cell response induced by mating with CD-fed males was blunted after mating with HFD-fed males, with 27% fewer CD4+ T cells, 26% fewer FOXP3+CD4+ regulatory T cells (Treg) cells, and 19% fewer CTLA4+ Treg cells, particularly within the NRP1+ thymic Treg cell population. These findings demonstrate that an obesogenic HFD alters the composition of seminal vesicle fluid and impairs seminal plasma capacity to elicit a favorable pro-tolerogenic immune response in females at conception.
Publisher: Wiley
Date: 12-11-2012
DOI: 10.2164/JANDROL.112.016535
Abstract: The ability of spermatozoa to generate reactive oxygen species (ROS) has been appreciated since the 1940s. It is a universal property of mature spermatozoa from all mammalian species and a major contributor to the oxidative stress responsible for defective sperm function. The mechanisms by which oxidative stress limits the functional competence of mammalian spermatozoa involve the peroxidation of lipids, the induction of oxidative DNA damage, and the formation of protein adducts. ROS production in these cells involves electron leakage from the sperm mitochondria, triggered by a multitude of factors that impede electron flow along the electron transport chain. The net result of mitochondrial ROS generation is to damage these organelles and initiate an intrinsic apoptotic cascade, as a consequence of which spermatozoa lose their motility, DNA integrity, and vitality. This pathway of programmed senescence also results in the exteriorization of phosphatidylserine, which may facilitate the silent phagocytosis of these cells in the aftermath of insemination, in turn influencing the female tract immune response to sperm antigens and future fertility. Despite the vulnerability of sperm to oxidative stress, it is also clear that normal sperm function depends on low levels of ROS generation in order to promote the signal transduction pathways associated with capacitation. Modulators of ROS generation by spermatozoa may therefore have clinical utility in regulating the fertilizing capacity of these cells and preventing the development of antisperm immunity. Achievement of these objectives will require a systematic evaluation of pro- and antioxidant strategies in vivo and in vitro.
Publisher: Elsevier BV
Date: 08-2003
DOI: 10.1016/S0165-0378(03)00052-4
Abstract: Conventional belief holds that an immune response to ejaculate antigens should interfere with fertilisation and establishment of pregnancy. However, emerging evidence now supports the opposing view-that insemination acts to activate maternal immune mechanisms exerting a positive effect on reproductive events. In a response well documented in rodents, semen triggers an influx of antigen-presenting cells into the female reproductive tract which process and present paternal ejaculate antigens to elicit activation of lymphocytes in the adaptive immune compartment. Transforming growth factor beta (TGFbeta), a cytokine present in abundance in seminal plasma, initiates this inflammatory response by stimulating the synthesis of pro-inflammatory cytokines and chemokines in uterine tissues. Lymphocyte activation is evident in lymph nodes draining the uterus and leads to hypo-responsiveness in T-cells reactive with paternal alloantigens. TGFbeta has potent immune-deviating effects and is likely to be the key agent in skewing the immune response against a Type-1 bias. Prior exposure to semen in the context of TGFbeta can be shown to be associated with enhanced fetal-placental development late in gestation. In this paper, we review the experimental basis for these claims and propose the hypothesis that, in women, the partner-specific protective effect of insemination in pre-ecl sia might be explained by induction of immunological hypo-responsiveness conferring tolerance to histocompatibility antigens present in the ejaculate and shared by the conceptus.
Publisher: Springer Science and Business Media LLC
Date: 03-12-2021
Publisher: AIP Publishing
Date: 15-10-2009
DOI: 10.1063/1.3253576
Abstract: Formation of defects in hexagonal and cubic boron nitride (h-BN and c-BN, respectively) under low-energy argon or nitrogen ion-bombardment has been studied by near-edge x-ray absorption fine structure (NEXAFS) around boron and nitrogen K-edges. Breaking of B–N bonds for both argon and nitrogen bombardment and formation of nitrogen vacancies, VN, has been identified from the B K-edge of both h-BN and c-BN, followed by the formation of molecular nitrogen, N2, at interstitial positions. The presence of N2 produces an additional peak in photoemission spectra around N 1s core level and a sharp resonance in the low-resolution NEXAFS spectra around N K-edge, showing the characteristic vibrational fine structure in high-resolution measurements. In addition, several new peaks within the energy gap of BN, identified by NEXAFS around B and N K-edges, have been assigned to boron or nitrogen interstitials, in good agreement with theoretical predictions. Ion bombardment destroys the cubic phase of c-BN and produces a phase similar to a damaged hexagonal phase.
Publisher: Wiley
Date: 08-02-2019
DOI: 10.1111/JPC.14402
Abstract: Anaemia of prematurity will affect 90% of all very preterm infants, resulting in at least one red blood cell (RBC) transfusion. A significant proportion of preterm infants require multiple transfusions over the course of hospital admission. Growing evidence supports an association between transfusion exposure and adverse neonatal outcomes. In adults, transfusion-associated sepsis, transfusion-related acute lung injury and haemolytic reactions are the leading causes of transfusion-related morbidity and mortality however, these are seldom recognised in newborns. The association between transfusion and adverse outcomes remains inconclusive. However, the evidence from preclinical studies demonstrates that RBC products can directly modulate immune cell function, a pathway termed transfusion-related immunomodulation (TRIM), which may provide a mechanism linking transfusion exposure with neonatal morbidities. Finally, we discuss the impact of TRIM on transfusion medicine, how we may address these issues and the emerging areas of research aimed at improving the safety of transfusions in this vulnerable population.
Publisher: Wiley
Date: 19-01-2022
Abstract: The seminal vesicles are male accessory sex glands that contribute the major portion of the seminal plasma in which mammalian spermatozoa are bathed during ejaculation. In addition to conveying sperm through the ejaculatory duct, seminal vesicle secretions support sperm survival after ejaculation, and influence the female reproductive tract to promote receptivity to pregnancy. Analysis of seminal vesicle fluid (SVF) composition by proteomics has proven challenging, due to its highly biased protein signature with a small subset of dominant proteins and the difficulty of solubilizing this viscous fluid. As such, publicly available proteomic datasets identify only 85 SVF proteins in total. To address this limitation, we report a new preparative methodology involving sequential solubilization of mouse SVF in guanidine hydrochloride, acetone precipitation, and analysis by label‐free mass spectrometry. Using this strategy, we identified 126 SVF proteins, including 83 previously undetected in SVF. Members of the seminal vesicle secretory protein family were the most abundant, accounting for 79% of all peptide spectrum matches. Functional analysis identified inflammation and formation of the vaginal plug as the two most prominent biological processes. Other notable processes included modulation of sperm function and regulation of the female reproductive tract immune environment. Together, these findings provide a robust methodological framework for future SVF studies and identify novel proteins with potential to influence both male and female reproductive physiology.
Publisher: The Endocrine Society
Date: 04-1991
Abstract: The effects of human interleukin-1 (IL-1) and IL-2 on human granulosa-luteal cell progesterone production were examined with or without hCG stimulation in vitro. Human granulosa-luteal cells were recovered from follicular fluid obtained from women undergoing in vitro fertilization procedures and cultured for up to 7 days before supernatant progesterone level measurement. Lymphokine-rich conditioned medium was prepared from mitogen-stimulated human peripheral blood leukocytes (HPL-CM). The influence of HPL-CM on both granulosa-luteal cell progesterone production and cell growth was inhibitory. In contrast, supernatants of the IL-2-producing cell line MLA-144 (MLA-CM) stimulated both basal progesterone secretion and cell proliferation. Human recombinant IL-2 (from 0.1-100 IU) alone did not change progesterone levels, compared to control values, after 24 h of cell culture. However, 1, 10, and 100 IU IL-2 significantly inhibited progesterone secretion from cells stimulated by 5 IU hCG (P less than 0.01). The enhanced progesterone levels stimulated by forskolin were also significantly inhibited by 10 IU IL-2 (P = 0.01). This effect was not mediated through decreased cAMP, since the forskolin-enhanced cAMP level was not influenced by IL-2, IL-1, with or without hCG, did not show any effect on progesterone production during either 24 or 48 h of cell culture. It is concluded that 1) human recombinant IL-2 significantly inhibits progesterone production stimulated by hCG in human granulosa-luteal cells 2) IL-2 also had a marked inhibitory effect on forskolin-induced progesterone release, but did not influence the increased cAMP level stimulated by forskolin 3) the inhibitory influence of IL-2 on progesterone synthesis may be down-stream in the signal transduction pathway from cAMP activation and 4) HPL-CM and MLA-CM produced inhibitory and stimulatory effects, respectively, on both basal and hCG-stimulated progesterone levels as well as on granulosa-luteal cell proliferation. These activities cannot be completely attributed to IL-2, and other mediators of leukocyte origin may, therefore, exist.
Publisher: Georg Thieme Verlag KG
Date: 07-2016
Publisher: American Association for the Advancement of Science (AAAS)
Date: 15-08-2014
Abstract: At fertilization, the gametes endow the embryo with a genomic blueprint, the integrity of which is affected by the age and environmental exposures of both parents. Recent studies reveal that parental history and experiences also exert effects through epigenomic information not contained in the DNA sequence, including variations in sperm and oocyte cytosine methylation and chromatin patterning, noncoding RNAs, and mitochondria. Transgenerational epigenetic effects interact with conditions at conception to program the developmental trajectory of the embryo and fetus, ultimately affecting the lifetime health of the child. These insights compel us to revise generally held notions to accommodate the prospect that biological parenting commences well before birth, even prior to conception.
Publisher: CSIRO Publishing
Date: 2009
DOI: 10.1071/RD08294
Abstract: Analysis of Tgfb1 null mutant mice has demonstrated that the cytokine transforming growth factor β1 (TGFB1) has essential non-redundant roles in fertility. The present study attempted to alleviate the infertility phenotype of Tgfb1 null mutant male mice by administration of exogenous TGFB1, either orally by colostrum feeding or subcutaneously by delivery of recombinant human latent TGFB1 (rhLTGFB1) via osmotic mini-pumps. Bovine colostrum and fresh unpasteurised bovine milk were found to be rich sources of TGFB1 and TGFB2 however, feeding Tgfb1 null mutant mice colostrum for 2 days failed to raise serum levels of TGFB1. Administration of rhLTGFB1 (~150 μg in total) over 14 days to Tgfb1 null mutant mice resulted in detectable TGFB1 in serum however, mean levels remained 10-fold less than in Tgfb1 heterozygous mice. After 7 days and 14 days of rhLTGFB1 administration, serum testosterone, spontaneous non-contact erections and mating behaviour were assessed. Despite the increased serum TGFB1, administration of rhLTGFB1 to Tgfb1 null mutant mice failed to improve these fertility parameters. It is concluded that sustained restoration of circulating latent TGFB1 to levels approaching the normal physiological range does not rescue the infertility phenotype caused by TGFB1 deficiency. Reproductive function in male Tgfb1 null mutant mice may not respond to systemic TGFB1 supplementation due to a requirement for local sources of TGFB1 at the site of action in the reproductive tract, or perturbed development during the neonatal period or puberty such that adult reproductive function is permanently impaired.
Publisher: Elsevier
Date: 2021
Publisher: Elsevier BV
Date: 02-2016
DOI: 10.1016/J.JRI.2015.11.005
Abstract: Investigating immune cell populations within various reproductive tissues commonly utilises flow cytometric methods. With advances in fluorophore technology and equipment capabilities, multiple cell types from a single tissue s le can be identified by using different combinations of cell surface markers to distinguish specific cell populations. Here a protocol optimized for mouse uterine tissue was used to show the proportional changes in dendritic cells, monocyte/macrophages, T and B cells, NK and NK T cells, and the granulocytes, neutrophils and eosinophils at each of the four stages of the estrous cycle. Importantly, we demonstrate that use of anti-SiglecF or assessment of FSC/SSC plots could be used to differentiate monocyte/macrophage and eosinophil populations that otherwise cannot be distinguished by use of the common combination of antibodies against F4/80 and CD11b. Our results clearly indicate that within the uterus a dynamic population of immune cells resides, with many cell types reaching peak abundance at estrus and metestrus phases of the cycle, consistent with their importance in the response to paternal antigens and/or pathogens encountered after insemination.
Publisher: Oxford University Press (OUP)
Date: 25-03-2004
Publisher: Elsevier BV
Date: 05-2017
DOI: 10.1038/MI.2016.85
Abstract: Infection-associated inflammatory stress during pregnancy is the most common cause of fetal growth restriction and/or miscarriage. Treatment strategies for protection of at-risk mothers are limited to a narrow range of vaccines, which do not cover the bulk of the common pathogens most frequently encountered. Using mouse models, we demonstrate that oral treatment during pregnancy with a microbial-derived immunomodulator (OM85), currently used clinically for attenuation of infection-associated airway inflammatory symptoms in infants-adults, markedly reduces risk for fetal loss/growth restriction resulting from maternal challenge with bacterial lipopolysaccharide or influenza. Focusing on LPS exposure, we demonstrate that the key molecular indices of maternal inflammatory stress, notably high levels of RANTES, MIP-1α, CCL2, KC, and G-CSF (granulocyte colony-stimulating factor) in gestational tissues/serum, are abrogated by OM85 pretreatment. Systems-level analyses conducted in parallel using RNASeq revealed that OM85 pretreatment selectively tunes LPS-induced activation in maternal gestational tissues for attenuated expression of TNF, IL1, and IFNG-driven proinflammatory networks, without constraining Type1-IFN-associated networks central to first-line antimicrobial defense. This study suggests that broad-spectrum protection-of-pregnancy against infection-associated inflammatory stress, without compromising capacity for efficient pathogen eradication, represents an achievable therapeutic goal.
Publisher: Elsevier BV
Date: 11-1992
DOI: 10.1016/S0015-0282(16)55438-7
Abstract: To examine the concentration of tumor necrosis factor alpha (TNF alpha) in human follicular fluid (FF) and its effects on cultured human granulosa-lutein cells. The concentration of TNF alpha in FF from hyperstimulated cycles and in conditioned media from cultured granulosa-lutein cells was measured by radioimmunoassay (RIA) and bioassay using L929 cells. The effects of recombinant human TNF alpha (rTNF alpha) on proliferation and production of progesterone (P) and prostaglandin (PG, PGE2, and PGF2 alpha) by cultured human granulosa-lutein cells were assessed. In vitro fertilization and embryo transfer (IVF-ET) program at Reproductive Medicine Unit, The Queen Elizabeth Hospital, Woodville, South Australia, Australia. Twenty-five women undergoing IVF-ET for tubal factor infertility. The concentration of immunoreactive TNF alpha in FF was 0.36 +/- 0.02 microgram/L, and there were no significant correlations between levels of TNF alpha and steroids or FF volume. Bioactivity for TNF alpha was considerably less. Immunoreactive or bioactive TNF alpha was not detected in conditioned media from granulosa-lutein cell culture. Recombinant human TNF alpha dose-dependently stimulated proliferation of cultured granulosa-lutein cells as measured by incorporation of 3H-thymidine, but in contrast to earlier reports, we were not able to demonstrate any effect of rTNF alpha on basal or human chorionic gonadotropin-stimulated P accumulation during culture periods of up to 72 hours. The accumulation of both PGE2 and PGF2 alpha was dose-dependently increased by rTNF alpha during a 48-hour incubation period. Time course studies revealed that maximal levels of both PGE2 and PGF2 alpha were reached within 12 hours of culture. Immunoreactive and bioactive TNF alpha is present in FF. Tumor necrosis factor alpha may have a physiological role in stimulating proliferation of follicular cells and PG production at the time of ovulation and formation of the corpus luteum.
Publisher: Elsevier BV
Date: 09-2012
Publisher: Public Library of Science (PLoS)
Date: 07-2014
Publisher: Oxford University Press (OUP)
Date: 07-2003
Publisher: Oxford University Press (OUP)
Date: 10-2008
DOI: 10.1095/BIOLREPROD.107.067272
Abstract: The cytokine-transforming growth factor beta1 (TGFB1) is implicated in development of the mammary gland through regulation of epithelial cell proliferation and differentiation during puberty and pregnancy. We compared mammary gland morphogenesis in virgin Tgfb1(+/+), Tgfb1(+/-), and Tgfb1(-/-) mice and transplanted Tgfb1(+/+) and Tgfb1(-/-) epithelium to determine the impact of TGFB1 deficiency on development. When mammary gland tissue was evaluated relative to the timing of puberty, invasion through the mammary fat pad of the ductal epithelium progressed similarly, irrespective of genotype, albeit fewer terminal end buds were observed in mammary glands from Tgfb1(-/-) mice. The terminal end buds appeared to be normal morphologically, and a comparable amount of epithelial proliferation was evident. When transplanted into wild-type recipients, however, Tgfb1(-/-) epithelium showed accelerated invasion compared with Tgfb1(+/+) epithelium. This suggests that the normal rate of ductal extension in Tgfb1(-/-) null mutant mice is the net result of impaired endocrine or paracrine support acting to limit the consequences of unrestrained epithelial growth. By adulthood, mammary glands in cycling virgin Tgfb1(-/-) mice were morphologically similar to those in Tgfb1(+/+) and Tgfb1(+/-) animals, with a normal branching pattern, and the tissue differentiated into early alveolar structures in the diestrous phase of the ovarian cycle. Transplanted mammary gland epithelium showed a similar extent of ductal branching and evidence of secretory differentiation of luminal cells in pregnancy. These results reveal two opposing actions of TGFB1 during pubertal mammary gland morphogenesis: autocrine inhibition of epithelial ductal growth, and endocrine or paracrine stimulation of epithelial ductal growth.
Publisher: Springer Science and Business Media LLC
Date: 09-04-2020
DOI: 10.1007/S00404-020-05532-3
Abstract: To evaluate implantation potential of cleavage-stage embryos cultured in medium containing 2 ng/ml granulocyte–macrophage colony-stimulating factor (GM-CSF) versus control medium, according to embryo morphological quality and then transferred on day 3. Explorative secondary data analysis of a multicenter, randomized, placebo-controlled, double-blinded prospective study of 1149 couples with embryo transfer after IVF/ICSI. This analysis includes a subgroup of 422 subjects with either single-embryo transfer (SET, N = 286) or double-embryo transfer of two embryos with equivalent morphological quality (DET, N = 136). Implantation rate and live birth rate were assessed according to category of morphological embryo quality on day 3. Culture with GM-CSF did not increase the implantation rate for embryos classified as poor quality. A trend towards greater benefit of GM-CSF on implantation and survival until live birth for top-quality embryos (TQEs) compared with poor-quality embryos was observed, although not statistically significant. For TQEs, the percentage of transferred embryos resulting in a live born baby was: 40.9 ± 5.3% (GM-CSF) versus 30.5 ± 4.6% (control) ( P = 0.24 odds ratio [OR] 1.43, 95% confidence interval [CI] 0.79–2.59), and for embryos with less than 6 cells at day 3 this same rate was: 7.4 ± 3.3% (GM-CSF) versus 12.0 ± 4.0% (control) ( P = 0.26 OR 0.53, 95% CI 0.17–1.61). This exploratory analysis is consistent with GM-CSF protecting morphologically normal embryos from culture-induced stress and does not support an effect of GM-CSF in rescuing poor-quality embryos. ClinicalTrials.gov identifier: NCT00565747.
Publisher: Springer Science and Business Media LLC
Date: 08-10-2021
DOI: 10.1186/S12864-021-07951-1
Abstract: The seminal vesicles synthesise bioactive factors that support gamete function, modulate the female reproductive tract to promote implantation, and influence developmental programming of offspring phenotype. Despite the significance of the seminal vesicles in reproduction, their biology remains poorly defined. Here, to advance understanding of seminal vesicle biology, we analyse the mouse seminal vesicle transcriptome under normal physiological conditions and in response to acute exposure to the reproductive toxicant acrylamide. Mice were administered acrylamide (25 mg/kg bw/day) or vehicle control daily for five consecutive days prior to collecting seminal vesicle tissue 72 h following the final injection. A total of 15,304 genes were identified in the seminal vesicles with those encoding secreted proteins amongst the most abundant. In addition to reproductive hormone pathways, functional annotation of the seminal vesicle transcriptome identified cell proliferation, protein synthesis, and cellular death and survival pathways as prominent biological processes. Administration of acrylamide elicited 70 differentially regulated (fold-change ≥1.5 or ≤ 0.67) genes, several of which were orthogonally validated using quantitative PCR. Pathways that initiate gene and protein synthesis to promote cellular survival were prominent amongst the dysregulated pathways. Inflammation was also a key transcriptomic response to acrylamide, with the cytokine, Colony stimulating factor 2 ( Csf2 ) identified as a top-ranked upstream driver and inflammatory mediator associated with recovery of homeostasis. Early growth response ( Egr1 ), C-C motif chemokine ligand 8 ( Ccl8 ), and Collagen, type V, alpha 1 ( Col5a1 ) were also identified amongst the dysregulated genes. Additionally, acrylamide treatment led to subtle changes in the expression of genes that encode proteins secreted by the seminal vesicle, including the complement regulator, Complement factor b ( Cfb ). These data add to emerging evidence demonstrating that the seminal vesicles, like other male reproductive tract tissues, are sensitive to environmental insults, and respond in a manner with potential to exert impact on fetal development and later offspring health.
Publisher: The Endocrine Society
Date: 27-08-2019
Abstract: Inflammation elicited by infection or noninfectious insults during gestation induces proinflammatory cytokines that can shift the trajectory of development to alter offspring phenotype, promote adiposity, and increase susceptibility to metabolic disease in later life. In this study, we use mice to investigate the utility of a small molecule Toll-like receptor (TLR)4 antagonist (+)-naloxone, the nonopioid isomer of the opioid receptor antagonist (−)-naloxone, for mitigating altered fetal metabolic programming induced by a modest systemic inflammatory challenge in late gestation. In adult progeny exposed to lipopolysaccharide (LPS) challenge in utero, male but not female offspring exhibited elevated adipose tissue, reduced muscle mass, and elevated plasma leptin at 20 weeks of age. Effects were largely reversed by coadministration of (+)-naloxone following LPS. When given alone without LPS, (+)-naloxone elicited accelerated postweaning growth and elevated muscle and fat mass in adult male but not female offspring. LPS induced expression of inflammatory cytokines Il1a, Il1b, Il6, Tnf, and Il10 in fetal brain, placental, and uterine tissues, and (+)-naloxone suppressed LPS-induced cytokine expression. Fetal sex-specific regulation of cytokine expression was evident, with higher Il1a, Il1b, Il6, and Il10 induced by LPS in tissues associated with male fetuses, and greater suppression by (+)-naloxone of Il6 in females. These data demonstrate that modulating TLR4 signaling with (+)-naloxone provides protection from inflammatory ersion of fetal developmental programming in utero, associated with attenuation of gestational tissue cytokine expression in a fetal sex-specific manner. The results suggest that pharmacologic interventions targeting TLR4 warrant evaluation for attenuating developmental programming effects of fetal exposure to maternal inflammatory mediators.
Publisher: Oxford University Press (OUP)
Date: 12-2002
DOI: 10.1095/BIOLREPROD.101.001503
Abstract: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is expressed in the female reproductive tract during early pregnancy and can promote the growth and development of preimplantation embryos in several species. We have demonstrated with in vitro experiments that the incidence of blastulation in human embryos is increased approximately twofold when GM-CSF is present in the culture medium. In the present study, we investigated the mechanisms underlying the embryotrophic actions of GM-CSF. Using reverse transcription-polymerase chain reaction and immunocytochemistry, expression of mRNA and protein of the GM-CSF-receptor alpha subunit (GM-Ralpha) was detected in embryos from the first-cleavage through blastocyst stages of development, but the GM-CSF-receptor beta common subunit (betac) could not be detected at any stage. When neutralizing antibodies reactive with GM-Ralpha were added to embryo culture experiments, the development-promoting effect of GM-CSF was ablated. In contrast, GM-CSF activity in embryos was not inhibited either by antibodies to betac or by E21R, a synthetic GM-CSF analogue that acts to antagonize betac-mediated GM-CSF signaling. Unexpectedly, E21R was found to mimic native GM-CSF in promoting blastulation. When embryos were assessed for apoptosis and cell number by confocal microscopy after TUNEL and propidium iodine staining, it was found that blastocysts cultured in GM-CSF contained 50% fewer apoptotic nuclei and 30% more viable inner cell mass cells. Together, these data indicate that GM-CSF regulates cell viability in human embryos and that this potentially occurs through a novel receptor mechanism that is independent of betac.
Publisher: The American Association of Immunologists
Date: 15-10-2022
Abstract: Pregnancy depends on a state of maternal immune tolerance mediated by CD4
Publisher: Elsevier BV
Date: 08-2010
DOI: 10.1016/J.JAUT.2010.03.002
Abstract: Antibodies reactive with the ovarian glycoprotein zona pellucida (ZP) have been linked with human female infertility. Anti-fertility vaccines that target ZP antigens have been utilized to restrict pest animal populations and their efficacy is associated with ovary-specific antibody induction. However, the necessity for zona pellucida-specific antibody in mediating infertility has not been examined in vivo. A recombinant mouse cytomegalovirus vaccine encoding murine zona pellucida 3 that induces rapid and complete infertility in BALB/c mice has been produced. The onset of infertility is temporally related to the presence of antibody sequestered into ovarian follicles and binding to the ZP of infected mice and the loss of mature follicles. When this vaccine was inoculated into immunoglobulin-deficient BALB/c mice with a null mutation in the immunoglobulin mu chain gene Igh-6, fertility was unaffected. Passive transfer of serum containing ZP3 antibodies also elicited transient infertility. Electron microscopy of ovarian tissue collected from ZP3-immunized immunocompetent mice demonstrated significant focal thinning of the zona pellucida (ZP) with reduced length and concentration of transzonal processes and many oocytes displayed evidence of injury. None of these changes were found in vaccinated immunoglobulin-deficient mice. These data confirm that ZP3-reactive antibody is necessary and sufficient to induce autoimmune-mediated follicular depletion and fertility suppression following the inoculation of this vaccine, and suggest that this is due to impaired zona pellucida formation. These findings have relevance in understanding the etiology of autoimmune ovarian disease in woman where anti-ZP antibodies are likely to have a causal role in infertility.
Publisher: Frontiers Media SA
Date: 12-04-2021
DOI: 10.3389/FENDO.2021.607539
Abstract: Endocrine disrupting compounds (EDCs) are prevalent and ubiquitous in our environment and have substantial potential to compromise human and animal health. Amongst the chronic health conditions associated with EDC exposure, dysregulation of reproductive function in both females and males is prominent. Human epidemiological studies demonstrate links between EDC exposure and infertility, as well as gestational disorders including miscarriage, fetal growth restriction, preecl sia, and preterm birth. Animal experiments show EDCs administered during gestation, or to either parent prior to conception, can interfere with gamete quality, embryo implantation, and placental and fetal development, with consequences for offspring viability and health. It has been presumed that EDCs operate principally through disrupting hormone-regulated events in reproduction and fetal development, but EDC effects on maternal immune receptivity to pregnancy are also implicated. EDCs can modulate both the innate and adaptive arms of the immune system, to alter inflammatory responses, and interfere with generation of regulatory T (Treg) cells that are critical for pregnancy tolerance. Effects of EDCs on immune cells are complex and likely exerted by both steroid hormone-dependent and hormone-independent pathways. Thus, to better understand how EDCs impact reproduction and pregnancy, it is imperative to consider how immune-mediated mechanisms are affected by EDCs. This review will describe evidence that several EDCs modify elements of the immune response relevant to pregnancy, and will discuss the potential for EDCs to disrupt immune tolerance required for robust placentation and optimal fetal development.
Publisher: UPV/EHU Press
Date: 2014
Abstract: The capacity of the immune system to maintain the integrity of the in idual requires recognition and control of entities identified as genetically distinct, or 'non-self'. In mammalian reproduction, the embryo and subsequent fetus and placenta are all recognized as non-self by the maternal immune system, and are vulnerable to immunological attack. An active system to prevent rejection must exist from when conceptus and maternal tissues first come into contact at implantation. Crucial mediators of immune protection are inducible regulatory T cells (Treg cells). Unless sufficient Treg cells are present in the endometrium, successful implantation and progression to pregnancy cannot ensue. This key role of Treg cells confers to the female immune system substantial capability to influence reproductive events, particularly around the time of conception and embryo implantation. While on the one hand this risks susceptibility to immune-based reproductive disorders, the potential evolutionary trade-off is the benefit of quality control to avoid poor reproductive outcomes. Here we summarize current knowledge of the factors required to establish a robust Treg cell response and an immune environment conducive to successful implantation and pregnancy. These factors include (a) appropriate cytokine balance (b) correct phenotype of endometrial leukocytes to enable Treg cell activation (c) sufficient estrogen and progesterone to stabilize and strengthen Treg cell phenotype, and (d) appropriate priming of Treg cell populations by male partner seminal fluid. Compromises in the quality of this immune adaptation at conception can influence the early embryo and either prevent implantation or impair placental morphogenesis. Failure to successfully establish Treg cell-mediated immune tolerance can result in poor fertility or impart long-term adverse consequences for the fetus and offspring.
Publisher: The Endocrine Society
Date: 05-2005
DOI: 10.1210/EN.2004-1260
Abstract: Growth factors secreted by the female reproductive tract promote development of the preimplantation embryo and potentially act as epigenetic determinants of postimplantation developmental competence and pregnancy outcome. In a comprehensive embryo transfer study in mice, we examined the late gestational and postnatal effects of embryo exposure to the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF), identified as a key physiological regulator of cell number and viability in mouse and human blastocysts. Embryo development in culture in the absence of GM-CSF restricted fetal growth, accelerated postnatal growth, and increased adult body mass and adiposity in offspring compared with in vivo-grown embryos, especially in males. Addition of GM-CSF to embryo culture medium increased the proportion of transferred embryos that generated viable progeny and alleviated the effects of in vitro culture on fetal and postnatal growth trajectory but did not prevent programming of adult obesity. Placental morphogenesis was modified by embryo culture, which inhibited development of labyrinthine exchange tissue and adversely altered some structural correlates of placental transfer function. GM-CSF reversed the effect of culture on labyrinthine growth and increased the surface area of placental trophoblast available for nutrient exchange. These findings indicate that the detrimental influence of embryo culture on fetal viability and growth may be largely mediated through altered placental morphogenesis and can be alleviated by GM-CSF. This demonstrates that embryonic exposure to GM-CSF is essential for normal placental development and fetal growth.
Publisher: Bioscientifica
Date: 08-2004
DOI: 10.1530/REP.1.00160
Abstract: In pigs, uterine exposure to the constituents of semen is known to increase litter size but the underlying physiological mechanisms remain undefined. Studies in rodents and humans implicate immune modulating moieties in seminal plasma as likely candidates, acting through enhancing the receptivity of the female tract. In this study, the acute and longer term effects of seminal plasma on cytokine expression and leukocyte abundance in the pig endometrium during early pregnancy have been characterised. The reproductive tracts of gonadotrophin-primed pre-pubertal gilts treated with intrauterine infusions of either pooled seminal plasma or phosphate-buffered saline (PBS) were retrieved at 34 h, or on day 5 and day 9 after treatment. Seminal plasma elicited an endometrial inflammatory infiltrate comprised of predominantly macrophages and major histocompatibility complex class II + -activated macrophages and dendritic cells. The abundance of these cells was greatest at the pre-ovulatory (34 h) time-point and their increase relative to PBS-treated tissues was maintained until day 9 after seminal plasma treatment. Seminal plasma induced the expression of the cytokines, granulocyte macrophage colony-stimulating factor, interleukin-6 and monocyte chemoattractant protein-1, and the eicosanoid-synthesising enzyme cyclo-oxygenase-2. Expression was maximal 34 h after treatment but altered expression patterns as a consequence of seminal plasma induction persisted through early pregnancy. These changes were accompanied by altered dynamics in pre-implantation embryo development with an increase in the number of embryos and in their viability after seminal plasma treatment. Together, these findings implicate factors in seminal plasma in programming the trajectory of uterine cytokine expression and leukocyte trafficking during early pregnancy and in regulating pre-implantation embryo development in the pig.
Publisher: Elsevier BV
Date: 06-2022
DOI: 10.1016/J.FERTNSTERT.2022.04.023
Abstract: Immune cells are essential for endometrial receptivity to embryo implantation and early placental development. They exert tissue-remodeling and immune regulatory roles-acting to promote epithelial attachment competence, regulate the differentiation of decidual cells, remodel the uterine vasculature, control and resolve inflammatory activation, and suppress destructive immunity to paternally inherited alloantigens. From a biological perspective, the endometrial immune response exerts a form of "quality control"-it promotes implantation success when conditions are favorable but constrains receptivity when physiological circumstances are not ideal. Women with recurrent implantation failure and recurrent miscarriage may exhibit altered numbers or disturbed function of certain uterine immune cell populations-most notably uterine natural killer cells and regulatory T cells. Preclinical and animal studies indicate that deficiencies or aberrant activation states in these cells can be causal in the pathophysiological mechanisms of infertility. Immune cells are, therefore, targets for diagnostic evaluation and therapeutic intervention. However, current diagnostic tests are overly simplistic and have limited clinical utility. To be more informative, they need to account for the full complexity and reflect the range of perturbations that can occur in uterine immune cell phenotypes and networks. Moreover, safe and effective interventions to modulate these cells are in their infancy, and personalized approaches matched to specific diagnostic criteria will be needed. Here we summarize current biological understanding and identify knowledge gaps to be resolved before the promise of therapies to target the uterine immune response can be fully realized.
Publisher: Wiley
Date: 14-05-2004
Publisher: Springer Science and Business Media LLC
Date: 09-11-2017
DOI: 10.1038/S41598-017-15085-2
Abstract: Zinc is an essential micronutrient in pregnancy and zinc deficiency impairs fetal growth. We used a mouse model of moderate zinc deficiency to investigate the physiological mechanisms by which zinc is important to placental morphogenesis and the maternal blood pressure changes during pregnancy. A 26% reduction in circulating zinc (P = 0.005) was exhibited in mice fed a moderately zinc-deficient diet. Zinc deficiency in pregnancy resulted in an 8% reduction in both near term fetal and placental weights (both P 0.0001) indicative of disrupted placental development and function. Detailed morphological analysis confirmed changes to the placental labyrinth microstructure. Continuous monitoring of maternal mean arterial pressure (MAP) revealed a late gestation decrease in the zinc-deficient dams. Differential expression of a number of regulatory genes within maternal kidneys supported observations on MAP changes in gestation. Increased MAP late in gestation is required to maintain perfusion of multiple placentas within rodent pregnancies. Decreased MAP within the zinc-deficient dams implies reduced blood flow and nutrient delivery to the placenta. These findings show that adequate zinc status is required for correct placental morphogenesis and appropriate maternal blood pressure adaptations to pregnancy. We conclude that insufficient maternal zinc intake from before and during pregnancy is likely to impact in utero programming of offspring growth and development largely through effects to the placenta and maternal cardiovascular system.
Publisher: Elsevier
Date: 2015
Publisher: Elsevier BV
Date: 07-2020
DOI: 10.1038/S41385-020-0255-0
Abstract: The immune-regulatory microRNA miR-155 is reduced in recurrent miscarriage, suggesting that miR-155 contributes to immune tolerance in pregnancy. Here we show miR-155 is induced in the uterine mucosa and draining lymph nodes (dLN) during the female immune response to male seminal fluid alloantigens. Mice with null mutation in miR-155 (miR-155
Publisher: Springer Science and Business Media LLC
Date: 07-11-2016
DOI: 10.1038/SREP36112
Abstract: Toll-like receptor 4 (TLR4) activation by bacterial infection, or by sterile inflammatory insult is a primary trigger of spontaneous preterm birth. Here we utilize mouse models to investigate the efficacy of a novel small molecule TLR4 antagonist, (+)-naloxone, the non-opioid isomer of the opioid receptor antagonist (−)-naloxone, in infection-associated preterm birth. Treatment with (+)-naloxone prevented preterm delivery and alleviated fetal demise in utero elicited by i.p. LPS administration in late gestation. A similar effect with protection from preterm birth and perinatal death, and partial correction of reduced birth weight and postnatal mortality, was conferred by (+)-naloxone administration after intrauterine administration of heat-killed E. coli . Local induction by E. coli of inflammatory cytokine genes Il1b , Il6, Tnf and Il10 in fetal membranes was suppressed by (+)-naloxone, and cytokine expression in the placenta, and uterine myometrium and decidua, was also attenuated. These data demonstrate that inhibition of TLR4 signaling with the novel TLR4 antagonist (+)-naloxone can suppress the inflammatory cascade of preterm parturition, to prevent preterm birth and perinatal death. Further studies are warranted to investigate the utility of small molecule inhibition of TLR-driven inflammation as a component of strategies for fetal protection and delaying preterm birth in the clinical setting.
Publisher: Elsevier BV
Date: 06-2009
DOI: 10.1016/J.CYTOGFR.2009.05.003
Abstract: Transforming growth factor beta 1 (TGFB1) is implicated as a key regulator of the development and cyclic remodelling characteristic of reproductive tissues. The physiological significance of TGFB1 in reproductive biology and fertility has been extensively examined in Tgfb1 null mutant mice. Genetic deficiency in TGFB1 causes perturbed functioning of the hypothalamic-pituitary-gonadal axis, inhibiting luteinising hormone (LH) synthesis and leading to downstream effects on testosterone production in males and estrous cycle abnormalities in females. Oocyte developmental incompetence, accompanied by early embryo arrest as well as altered pubertal mammary gland morphogenesis are observed. In addition to LH and testosterone deficiency, male Tgfb1 null mice demonstrate complete inability to mate with females, associated with failure to initiate and/or sustain successful penile intromission or ejaculation. These studies demonstrate the profound significance of TGFB1 in male and female reproductive physiology, and provide a foundation for exploring the significance of this cytokine in human infertility and sexual dysfunction.
Publisher: Springer Science and Business Media LLC
Date: 16-08-2021
DOI: 10.1038/S41598-021-95213-1
Abstract: Maternal immune adaptation to accommodate pregnancy depends on sufficient availability of regulatory T (Treg) cells to enable embryo implantation. Toll-like receptor 4 is implicated as a key upstream driver of a controlled inflammatory response, elicited by signals in male partner seminal fluid, to initiate expansion of the maternal Treg cell pool after mating. Here, we report that mice with null mutation in Tlr4 ( Tlr4 −/− ) exhibit impaired reproductive outcomes after allogeneic mating, with reduced pregnancy rate, elevated mid-gestation fetal loss, and fetal growth restriction, compared to Tlr4 +/+ wild-type controls. To investigate the effects of TLR4 deficiency on early events of maternal immune adaptation, TLR4-regulated cytokines and immune regulatory microRNAs were measured in the uterus at 8 h post-mating by qPCR, and Treg cells in uterus-draining lymph nodes were evaluated by flow cytometry on day 3.5 post-coitum. Ptgs2 encoding prostaglandin-endoperoxide synthase 2, cytokines Csf2 , Il6 , Lif, and Tnf , chemokines Ccl2 , Cxcl1 , Cxcl2 , and Cxcl10 , and microRNAs miR-155 , miR-146a , and miR-223 were induced by mating in wild-type mice, but not, or to a lesser extent, in Tlr4 −/− mice. CD4 + T cells were expanded after mating in Tlr4 +/+ but not Tlr4 −/− mice, with failure to expand peripheral CD25 + FOXP3 + NRP1 − or thymic CD25 + FOXP3 + NRP1 + Treg cell populations, and fewer Treg cells expressed Ki67 proliferation marker and suppressive function marker CTLA4. We conclude that TLR4 is an essential mediator of the inflammation-like response in the pre-implantation uterus that induces generation of Treg cells to support robust pregnancy tolerance and ensure optimal fetal growth and survival.
Publisher: MDPI AG
Date: 25-12-2020
DOI: 10.3390/NU12010061
Abstract: High amylose wheat (HAW) has a higher resistant starch content and lower glycaemic index than standard amylose wheat (SAW), which may be associated with health benefits. This study aimed to determine the effects of replacing SAW with HAW on metabolic and reproductive parameters in male and female mice. Male and female C57BL/6 mice were randomly ided into groups (n = 8/group/sex) and fed either a SAW65 (65% SAW w/w control), HAW35 (35% HAW w/w), HAW50 (50% HAW w/w) or HAW65 (65% HAW w/w) diet for eight weeks. In male but not female, the HAW65 group had a lower abdominal circumference, relative total fat mass, relative gonadal fat mass and plasma leptin concentration compared to the HAW35 group. There were no differences in fasting blood glucose concentrations or plasma concentrations of cholesterol, triglycerides or non-esterified fatty acids between groups in either males or females. The HAW-fed males had a higher testicular weight and HAW-fed females spent less time in diestrus and a longer time in metestrus compared to the SAW-fed mice. Higher dietary intake of HAW appears to reduce abdominal fat deposition compared to the lower level of HAW in a sexually dimorphic manner. The impacts on reproductive parameters in the HAW-fed mice require further investigation.
Publisher: Elsevier BV
Date: 03-2013
Publisher: Elsevier BV
Date: 10-2019
Publisher: Springer Science and Business Media LLC
Date: 11-01-2017
Publisher: Wiley
Date: 06-1997
DOI: 10.1111/J.1600-0897.1997.TB00257.X
Abstract: Factors in seminal plasma stimulate an intense but transient inflammatory response in the murine endometrium at mating. The aim of our current studies is to delineate the cytokine-leukocyte interactions comprising this response and to elucidate the significance of these events in changes in the maternal immune system and as determinants of pregnancy outcome. We have reviewed our recent findings. Transforming growth factor (TGF)-beta1 has been identified as the inflammation-inducing moiety in seminal plasma. Seminal TGFbeta1 initiates endometrial leukocyte infiltration by up-regulating epithelial cell expression of granulocyte-macrophage colony-stimulating factor. Other cytokines and chemokines including regulated and normal T-cell expressed and secreted (RANTES), macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and monocyte chemotactic protein-1 are also implicated as mediators of macrophage and granulocyte recruitment and activation. One consequence of this inflammatory response is the induction of a transient state of hyporesponsiveness to paternal major histocompatibility class I antigens. Our studies suggest that semen may play a critical role in providing the antigenic and environmental signals necessary to initiate an appropriate maternal immune response to the conceptus during pregnancy.
Publisher: Elsevier BV
Date: 02-2007
DOI: 10.1016/J.JRI.2006.06.003
Abstract: A erse array of cytokines is implicated in regulating the immune adaptation and endometrial tissue remodelling events that facilitate successful embryo implantation and early placental development. The aim of this study was to evaluate expression of mRNAs encoding a panel of immunoregulatory cytokines in the endometrium of fertile women and women experiencing recurrent miscarriage using highly sensitive, quantitative RT-PCR assays. Endometrial biopsies were collected during the mid-secretory phase of the menstrual cycle from women classified as proven fertile (control n=12) and women experiencing unexplained recurrent miscarriage (RM n=9). Reduced IL-6 mRNA and reduced IL-1alpha mRNA were independently associated with recurrent miscarriage. Altered expression was evident after accounting for variation in the composition of endometrial biopsies by normalization of data to epithelial and mesenchymal cell-specific transcripts, cytokeratin-18 mRNA and vimentin mRNA, respectively. The relative abundance of mRNAs encoding LIF, GM-CSF, IFNgamma, IL-1beta, IL-4, IL-5, IL-10, IL-12p40, TNFalpha, TGFbeta1, TGFbeta2 and TGFbeta3 were not altered in recurrent miscarriage tissue. Associations between expression of IL-10, LIF, GM-CSF and TGFbeta2 suggest that regulatory circuits link the transcription of these cytokine genes. Inadequate expression of IL-6 and IL-1alpha mRNAs in endometrial tissue may predispose to recurrent miscarriage through a perturbed maternal immune response, effects on decidual tissue remodeling and angiogenesis, or dysregulated trophoblast differentiation and invasion. Quantitative RT-PCR assays for these cytokines in endometrial biopsies may be a realistic strategy for development of novel diagnostics for predisposition to recurrent miscarriage.
Publisher: The Endocrine Society
Date: 03-01-2019
Abstract: Despite extensive searches for novel noninvasive diagnostics, laparoscopy remains the reference test for endometriosis. Circulating miRNAs are purported endometriosis biomarkers however, the miRNA species and their diagnostic accuracy differ between studies and have not been validated in independent cohorts. Identify endometriosis-specific plasma miRNAs and determine their diagnostic test accuracy. Two university-based, public hospitals and a private gynecology practice in Australia. Four phases: (i) Explorative phase. Plasma miRNA menstrual cycle fluctuations were evaluated in women with endometriosis and asymptomatic controls (n = 16). (ii) Biomarker discovery. Endometriosis-specific plasma miRNAs were identified in (a) women with endometriosis and asymptomatic controls (n = 16) and (b) women with and without surgically defined endometriosis (n = 20). (iii) Biomarker selection. Plasma miRNAs with the best diagnostic potential for endometriosis were selected in a surgically defined selection cohort (n = 78). (iv) Biomarker validation. The diagnostic test accuracy of these miRNAs was calculated in an independent, surgically defined validation cohort (n = 119). Forty-nine miRNAs were differentially expressed in women with endometriosis. Nine maintained dysregulation in the selection cohort, but only three (miR-155, miR574-3p and miR139-3p) did so in the validation cohort. Combined, these three miRNAs demonstrated a sensitivity and specificity of 83% and 51%, respectively. Plasma miRNAs demonstrated modest sensitivity and specificity as diagnostic tests or triage tools for endometriosis. Other groups' findings were not replicated and accorded poorly with our results. Circulating miRNAs demonstrate diagnostic potential, but stringent, standardized methodological approaches are required for the development of a clinically applicable tool.
Publisher: The Endocrine Society
Date: 04-07-2022
Abstract: Regulatory T (Treg) cells are a specialized CD4+ T cell subpopulation that are essential for immune homeostasis, immune tolerance, and protection against autoimmunity. There is evidence that sex-steroid hormones estrogen and progesterone modulate Treg cell abundance and phenotype in women. Since natural oscillations in these hormones are modified by hormonal contraceptives, we examined whether oral contraception (OC) use impacts Treg cells and related T cell populations. T cells were analyzed by multiparameter flow cytometry in peripheral blood collected across the menstrual cycle from healthy women either using OC or without hormonal contraception and from age-matched men. Compared to naturally cycling women, women using OC had fewer Treg cells and an altered Treg cell phenotype. Notably, Treg cells exhibiting a strongly suppressive phenotype, defined by high FOXP3, CD25, Helios, HLADR, CTLA4, and Ki67, comprised a lower proportion of total Treg cells, particularly in the early- and mid-cycle phases. The changes were moderate compared to more substantial differences in Treg cells between women and men, wherein women had fewer Treg cells—especially of the effector memory Treg cell subset—associated with more T helper type 1 (Th1) cells and CD8+ T cells and lower Treg:Th1 cell and Treg:CD8+ T cell ratios than men. These findings imply that OC can modulate the number and phenotype of peripheral blood Treg cells and raise the possibility that Treg cells contribute to the physiological changes and altered disease susceptibility linked with OC use.
Publisher: Oxford University Press (OUP)
Date: 22-02-2019
Abstract: The change from the state of pregnancy to the state of parturition, which we call uterine transitioning, requires the actions of inflammatory mediators and results in an activated uterus capable of performing the physiology of labor. Interleukin (IL)-1β and prostaglandin (PG)F2α are two key mediators implicated in preparing the uterus for labor by regulating the expression of uterine activation proteins (UAPs) and proinflammatory cytokines and chemokines. To investigate this process, primary human myometrial smooth muscle cells (HMSMC) isolated from the lower segment of women undergoing elective cesarean sections at term (not in labor) were used to test the inflammatory cytokine and UAP outputs induced by PGF2α and IL-1β alone or in sequential combinations. PGF2α and IL-1β regulate mRNA abundance of the PGF2α receptor FP, the IL-1 receptor system, interleukin 6, and other UAPs (OXTR, COX2), driving positive feedback interactions to further lify their own proinflammatory effects. Sequential stimulation of HMSMC by PGF2α and IL-1β in either order results in lified upregulation of IL-6 and COX-2 mRNA and protein, compared to their effects in idually. These profound increases were unique to myometrium and not observed with stimulation of human fetal membrane explants. These results suggest that PGF2α and IL-1β act cooperatively upstream in the birth cascade to maximize lification of IL-6 and COX-2, to build inflammatory load and thereby promote uterine transition. Targeting PGF2α or IL-1β, their actions, or intermediates (e.g. IL-6) would be an effective therapeutic intervention for preterm birth prevention or delay.
Publisher: Elsevier BV
Date: 08-2001
Publisher: Wiley
Date: 07-2011
DOI: 10.1111/J.1600-0897.2011.01039.X
Abstract: The peri-conceptual environment influences the early embryo to impart long-term consequences for the fetus and neonate however, the underlying mechanisms are not well defined. We argue that the cytokine network acting in the female reproductive tract during the pre- and peri-implantation period integrates environmental information to program the embryo and fine-tune the maternal immune response and endometrial remodelling to determine implantation success. As well as sex steroid hormones and male seminal fluid factors, female tract cytokines are influenced by agents signalling via the Toll-like receptors including the microbiome and a plethora of metabolic, chemical and other stressors. In mouse models, an altered peri-conceptual cytokine environment induced by cytokine deficiency, inflammatory insults or dysregulated seminal fluid signalling is associated with adverse effects on embryo development, pregnancy viability and reproductive outcome. The cytokine network provides a pivotal mechanism through which environmental factors influence both embryo development and receptivity of the uterus.
Publisher: Oxford University Press (OUP)
Date: 12-2000
DOI: 10.1093/HUMREP/15.12.2653
Abstract: Intercourse during an IVF cycle has the potential to improve pregnancy rates since exposure to semen is reported to promote embryo development and implantation in animals. Conversely, coitus-induced uterine contractions or introduction of infection may have a detrimental effect. A multicentre prospective randomized control trial was conducted to determine if intercourse during the peri-transfer period of an IVF cycle has any influence on pregnancy success. Participants undergoing thawed embryo transfer (Australian centre) or fresh embryo transfers (Spanish centres) were randomized either to abstain or to engage in vaginal intercourse around the time of embryo transfer. The transfer of 1343 embryos during 478 cycles of IVF resulted in 107 pregnancies (22.4%), with 125 viable embryos remaining by 6-8 weeks gestation. There was no significant difference between the intercourse and abstain groups in relation to the pregnancy rate (23.6 and 21.2% respectively), but the proportion of transferred embryos that were viable at 6-8 weeks was significantly higher in women exposed to semen compared to those who abstained (11.01 versus 7.69 viable embryos per 100 transferred embryos, P = 0.036, odds ratio 1.48, 95% confidence interval 1.01-2.19). Hence exposure to semen around the time of embryo transfer increases the likelihood of successful early embryo implantation and development.
Publisher: Oxford University Press (OUP)
Date: 10-2004
Publisher: American Society for Clinical Investigation
Date: 08-06-2023
Publisher: Springer International Publishing
Date: 2015
DOI: 10.1007/978-3-319-18881-2_6
Abstract: Carriage of sperm is not the only function of seminal fluid in mammals. Studies in mice show that at conception, seminal fluid interacts with the female reproductive tract to induce responses which influence whether or not pregnancy will occur, and to set in train effects that help shape subsequent fetal development. In particular, seminal fluid initiates female immune adaptation processes required to tolerate male transplantation antigens present in seminal fluid and inherited by the conceptus. A tolerogenic immune environment to facilitate pregnancy depends on regulatory T cells (Treg cells), which recognise male antigens and function to suppress inflammation and immune rejection responses. The female response to seminal fluid stimulates the generation of Treg cells that protect the conceptus from inflammatory damage, to support implantation and placental development. Seminal fluid also elicits molecular and cellular changes in the oviduct and endometrium that directly promote embryo development and implantation competence. The plasma fraction of seminal fluid plays a key role in this process with soluble factors, including TGFB, prostaglandin-E, and TLR4 ligands, demonstrated to contribute to the peri-conception immune environment. Recent studies show that conception in the absence of seminal plasma in mice impairs embryo development and alters fetal development to impact the phenotype of offspring, with adverse effects on adult metabolic function particularly in males. This review summarises our current understanding of the molecular responses to seminal fluid and how this contributes to the establishment of pregnancy, generation of an immune-regulatory environment and programming long-term offspring health.
Publisher: Elsevier BV
Date: 08-2011
Publisher: Elsevier BV
Date: 08-2011
Publisher: Elsevier BV
Date: 10-2002
DOI: 10.1016/S0165-0378(02)00042-6
Abstract: Seminal plasma is increasingly recognised as contributing to the reproductive process in roles apart from that of providing nutritive support and transport for spermatozoa. Seminal components elicit inflammatory responses in the female reproductive tract, including altered patterns of cytokine secretion, which have consequences for early embryo development and implantation. This review examines evidence, generated principally in the porcine model, for a more recently recognized role for seminal plasma in regulating the temporal kinetics of ovulation, corpus luteum development and steroid production in the ovary. Molecular mechanisms that operate to facilitate communication via a novel semen-uterine-ovarian axis are postulated. A better understanding of these events may facilitate development of strategies to ensure maximal fertility and reduce embryo mortality in the pig and other polyovular species.
Publisher: Elsevier BV
Date: 1992
DOI: 10.1016/0952-7915(92)90031-9
Abstract: Insights derived from recent studies employing rodent models demonstrate that the synthesis of pluripotent cytokines is an important function of resident cells in the female reproductive tract. Through steroid hormone regulated secretion of these mediators, resident cells appear to coordinate the recruitment and action of leukocytes that are centrally implicated in the dramatic remodelling processes characteristic of reproductive events.
Publisher: Oxford University Press (OUP)
Date: 07-2009
Publisher: BMJ
Date: 23-01-2023
DOI: 10.1136/ARCHDISCHILD-2022-324531
Abstract: To evaluate the association of donor sex with transfusion-associated recipient immune responses in preterm newborns receiving unwashed and washed blood. A cohort study using data collected during the Effect of Washed versus Unwashed Packed Red Blood Cell Transfusion on Immune Responses in the Extremely Preterm Newborn randomised trial. Participants were recruited from two South Australian hospitals between September 2015 and December 2020. Preterm newborns ( weeks). Transfusion with unwashed and washed packed red blood cells (PRBCs) from either exclusively male or any female donor for the first three transfusions. The primary outcome was the change from baseline in post-transfusion plasma cytokine concentrations, specifically interferon gamma, interleukin (IL)-1β, IL-6, IL-8, IL-10, IL-12, IL-17A and tumour necrosis factor (TNF). In total, 153 newborns were evaluated. By the third transfusion, the magnitude of pretransfusion to post-transfusion change in cytokines between the groups differed for IL-6 (p=0.003), IL-12 (p=0.008), IL-17A (p=0.003) and TNF (p=0.007). On post hoc comparison, compared with the unwashed–any female donor group, IL-6 (p .05), IL-12 (p .05) and IL-17A (p .01) were lower in the washed–exclusively male donor group, and IL-6 (p .01), IL-12 (p .05) and TNF (p .01) were lower in the washed–any female donor group. These findings suggest that transfusion with unwashed PRBCs from female donors is associated with an increased recipient immune response, an effect that can be ameliorated with pretransfusion washing. Larger randomised controlled studies confirming this mechanistic link between donor sex and transfusion-associated morbidity are warranted. ACTRN12613000237785.
Publisher: Oxford University Press (OUP)
Date: 25-05-0001
Abstract: Do seminal plasma pro-inflammatory cytokines interferon-γ (IFNG) and C-X-C motif chemokine ligand 8 (CXCL8) vary within in idual men over time? IFNG exhibits substantial variation that is independent of duration of abstinence but correlates with lipopolysaccharide (LPS) content, while CXCL8 varies moderately in association with duration of abstinence. Pro-inflammatory cytokines IFNG and CXCL8 in seminal fluid can adversely impact male and female fertility. Other cytokines as well as sperm parameters fluctuate considerably within in iduals over time, but whether IFNG and CXCL8 vary similarly, and the determinants of variance, are unknown. Between two and seven semen s les were collected from 14 proven fertile donors at 6-10 week intervals over the course of ~12 months, to assess variation over time in cytokines and LPS, and to investigate relationships with sperm parameters and possible regulatory factors. The concentrations and total amounts per ejaculate of IFNG and CXCL8 were determined using commercial ELISA. Sperm parameters were assessed according to World Health Organization (WHO) IV standards and LPS was measured by limulus amebocyte lysate (LAL) assay. Mixed model analysis was utilized to determine the relative contribution of between- and within-in idual factors in explaining variance. Relationships between cytokines, LPS and sperm parameters, as well as effect of age and duration of abstinence, were investigated by correlation analysis. Within-in idual variability contributed to total variance particularly for both IFNG, CXCL8 and LPS, and was a stronger determinant than between-in idual variability for IFNG and LPS. Normal sperm motility correlated inversely with CXCL8, and sperm concentration correlated inversely with LPS. Duration of abstinence was a determinant of total CXCL8, but not IFNG or LPS. Associations between LPS, IFNG and CXCL8 suggest IFNG and perhaps CXCL8 are influenced by microbial populations. A limited number of donors from a single clinic were investigated. Clinical information on complete microbiology, BMI, nutrition, smoking and other lifestyle factors was unavailable. Further studies are required to determine whether the findings can be generalized to larger populations and different ethnicities. These data reveal substantial variation over time in pro-inflammatory seminal fluid cytokines and imply existence of microbial or other environmental regulatory factors. This study was supported by grants from the National Health and Medical Research Council of Australia. The authors have no competing interests to disclose.
Publisher: Oxford University Press (OUP)
Date: 15-11-2018
Publisher: Wiley
Date: 12-08-2008
DOI: 10.1038/ICB.2008.53
Abstract: The Mucosal Immunology Special Interest Group (SIG-MI) of the Australasian Society of Immunology was formed 14 years ago and has run regular symposia and workshops in conjunction with the Australasian Society of Immunology since that time. In December 2007 the Mucosal Immunology Special Interest Group held a 1-day satellite workshop in conjunction with the annual Australasian Society of Immunology scientific meeting in Sydney to celebrate the decade since hosting the 9th International Congress of Mucosal Immunology (9-ICMI) in 1997, which was also held in Sydney. The meeting that was attended by 65 delegates focussed on 4 session themes: reproductive immunology, respiratory immunology, mucosal immunology of the gastrointestinal tract and mucosal vaccines.
Publisher: Elsevier BV
Date: 10-1996
Publisher: Cambridge University Press
Date: 31-01-2019
Publisher: Oxford University Press (OUP)
Date: 22-09-2006
Abstract: Polycystic ovary syndrome (PCOS) affects 5-10% of reproductive-aged women and is commonly associated with anovulatory infertility. Leukocytes, together with granulosa cells, may contribute to the pathogenesis of PCOS via their ability to secrete an array of cytokines implicated in follicle growth. The aim of this study was to examine leukocyte subtypes in follicular phase ovaries and to quantify cytokine and chemokine mRNA expression in follicular fluid cells obtained at the time of oocyte retrieval before IVF in women with and without PCOS. Ovaries were immunostained for various leukocyte markers [CD3, CD4, CD14, CD15, CD45, CD45RA, CD45RO, CD57 and major histocompatibility complex (MHC) class II]. In addition, follicular fluid cells were subjected to quantitative RT-PCR to evaluate colony-stimulating factor-1 (CSF-1), granulocyte-macrophage (GM)-CSF, interleukins (IL-1beta, IL-6, IL-8 and IL-10), monocyte chemotactic protein (MCP-1) and tumour necrosis factor (TNFalpha) mRNA expression relative to beta-actin. CD45RO+ cells (activated/memory T lymphocytes) were reduced by 60% in the theca layer of follicles from PCOS women. The relative abundance of macrophages and neutrophils was unchanged. Cytokine and chemokine mRNA transcripts examined were not affected by PCOS status. There was an association between high BMI and high TNFalpha and low IL-6 mRNA expression in follicular cells. IL-6 expression was higher in women who subsequently achieved pregnancy. T lymphocytes potentially play a role in the local pathological mechanisms of PCOS. Further studies are required to identify their contribution to the aetiology of this common condition.
Publisher: Wiley
Date: 25-09-2002
DOI: 10.1002/BIES.10155
Abstract: Members of the transforming growth factor beta (TGFbeta) family are pleiotropic cytokines with key roles in tissue morphogenesis and growth. TGFbeta1, TGFbeta2 and TGFbeta3 are abundant in mammalian reproductive tissues, where development and cyclic remodelling continue in post-natal and adult life. Potential roles for TGFbeta have been identified in gonad and secondary sex organ development, spermatogenesis and ovarian function, immunoregulation of pregnancy, embryo implantation and placental development. However, better tools must now be employed to map more precisely essential functions and the regulatory networks governing their activity. Gene ablation and transgenic models are expected to provide novel insights into distinct physiological activities for each TGFbeta isoform in normal reproductive function and reproductive pathologies. It is also necessary to consider the mechanisms controlling TGFbeta activation from latent precursor forms, and receptor and binding protein expression. Smad intracellular signalling circuitry and modulation by environmental stimuli through cross-talk with other signal transduction pathways will further constrain TGFbeta action. This review examines existing evidence for TGFbeta1, TGFbeta2 and TGFbeta3 regulation of male and female reproductive biology, and highlights prospects for future research.
Publisher: Cambridge University Press
Date: 27-03-2014
Publisher: Wiley
Date: 09-2014
DOI: 10.1111/RDA.12383
Abstract: Seminal fluid delivered to the female reproductive tract at coitus not only promotes the survival and fertilizing capacity of spermatozoa, but also contains potent signalling agents that influence female reproductive physiology to improve the chances of conception and reproductive success. Male to female seminal fluid signalling occurs in rodents, domestic and livestock animals, and all other mammals examined to date. Seminal plasma is instrumental in eliciting the female response, by provision of cytokines and prostaglandins synthesized in the male accessory glands. These agents bind to receptors on target cells in the cervix and uterus, activating changes in gene expression leading to functional adaptations in the female tissues. Sperm also interact with female tract cells, although the molecular basis of this interaction is not yet defined. The consequences are increased sperm survival and fertilization rates, conditioning of the female immune response to tolerate semen and the conceptus, and molecular and cellular changes in the endometrium that facilitate embryo development and implantation. Studies in porcine, equine, bovine, ovine and canine species all show evidence of male-female signalling function for seminal fluid. There are variations between species that relate to their different reproductive strategies and behaviours, particularly the site of seminal fluid deposition and female reproductive tract anatomy. Although the details of the molecular mechanisms require more study, the available data are consistent with both the sperm and plasma fractions of seminal fluid acting in a synergistic fashion to activate inflammation-like responses and downstream female tract changes in each of these species. Insight into the biological function and molecular basis of seminal fluid signalling in the female will inform new interventions and management practices to support optimal reproductive outcomes in domestic, livestock and endangered animal species.
Publisher: Springer Science and Business Media LLC
Date: 08-08-2018
DOI: 10.1038/S41598-018-30087-4
Abstract: Antenatal inflammation as seen with chorioamnionitis is harmful to foetal/neonatal organ development including to eyes. Although the major pro-inflammatory cytokine IL-1β participates in retinopathy induced by hyperoxia (a predisposing factor to retinopathy of prematurity), the specific role of antenatal IL-1β associated with preterm birth (PTB) in retinal vasculopathy (independent of hyperoxia) is unknown. Using a murine model of PTB induced with IL-1β injection in utero , we studied consequent retinal and choroidal vascular development in this process we evaluated the efficacy of IL-1R antagonists. Eyes of foetuses exposed only to IL-1β displayed high levels of pro-inflammatory genes, and a persistent postnatal infiltration of inflammatory cells. This prolonged inflammatory response was associated with: (1) a marked delay in retinal vessel growth (2) long-lasting thinning of the choroid and (3) long-term morphological and functional alterations of the retina. Antenatal administration of IL-1R antagonists – 101.10 (a modulator of IL-1R) more so than Kineret (competitive IL-1R antagonist) – prevented all deleterious effects of inflammation. This study unveils a key role for IL-1β, a major mediator of chorioamnionitis, in causing sustained ocular inflammation and perinatal vascular eye injury, and highlights the efficacy of antenatal 101.10 to suppress deleterious inflammation.
Publisher: Springer Science and Business Media LLC
Date: 24-03-2021
DOI: 10.1186/S13058-021-01417-8
Abstract: Transforming growth factor beta1 (TGFB1) is a multi-functional cytokine that regulates mammary gland development and cancer progression through endocrine, paracrine and autocrine mechanisms. TGFB1 also plays roles in tumour development and progression, and its increased expression is associated with an increased breast cancer risk. Macrophages are key target cells for TGFB1 action, also playing crucial roles in tumourigenesis. However, the precise role of TGFB-regulated macrophages in the mammary gland is unclear. This study investigated the effect of attenuated TGFB signalling in macrophages on mammary gland development and mammary cancer susceptibility in mice. A transgenic mouse model was generated, wherein a dominant negative TGFB receptor is activated in macrophages, in turn attenuating the TGFB signalling pathway specifically in the macrophage population. The mammary glands were assessed for morphological changes through wholemount and H& E analysis, and the abundance and phenotype of macrophages were analysed through immunohistochemistry. Another cohort of mice received carcinogen 7,12-dimethylbenz(a)anthracene (DMBA), and tumour development was monitored weekly. Human non-neoplastic breast tissue was also immunohistochemically assessed for latent TGFB1 and macrophage marker CD68. Attenuation of TGFB signalling resulted in an increase in the percentage of alveolar epithelium in the mammary gland at dioestrus and an increase in macrophage abundance. The phenotype of macrophages was also altered, with inflammatory macrophage markers iNOS and CCR7 increased by 110% and 40%, respectively. A significant decrease in DMBA-induced mammary tumour incidence and prolonged tumour-free survival in mice with attenuated TGFB signalling were observed. In human non-neoplastic breast tissue, there was a significant inverse relationship between latent TGFB1 protein and CD68-positive macrophages. TGFB acts on macrophage populations in the mammary gland to reduce their abundance and d en the inflammatory phenotype. TGFB signalling in macrophages increases mammary cancer susceptibility potentially through suppression of immune surveillance activities of macrophages.
Publisher: Frontiers Media SA
Date: 15-09-2020
Publisher: Elsevier BV
Date: 06-2009
DOI: 10.1016/J.JRI.2009.01.001
Abstract: The inaugural International Conference on Reproductive Immunology was hosted by the Hospital and Institute of Obstetrics and Gynaecology, Fudan University in Shanghai, People's Republic of China, in late August 2008. The meeting showcased cutting-edge basic and clinical research on the immunobiology of reproductive processes from several research groups in China, and also featured a number of international leaders in the field. This report describes some of the highlights of the meeting.
Publisher: The American Association of Immunologists
Date: 12-2010
Abstract: Uterine dendritic cells (DCs) are critical for activating the T cell response mediating maternal immune tolerance of the semiallogeneicfetus. GM-CSF (CSF2), a known regulator of DCs, is synthesized by uterine epithelial cells during induction of tolerance in early pregnancy. To investigate the role of GM-CSF in regulating uterine DCs and macrophages, Csf2-null mutant and wild-type mice were evaluated at estrus, and in the periconceptual and peri-implantation periods. Immunohistochemistry showed no effect of GM-CSF deficiency on numbers of uterine CD11c+ cells and F4/80+ macrophages at estrus or on days 0.5 and 3.5 postcoitum, but MHC class II+ and class A scavenger receptor+ cells were fewer. Flow cytometry revealed reduced CD80 and CD86 expression by uterine CD11c+ cells and reduced MHC class II in both CD11c+ and F4/80+ cells from GM-CSF–deficient mice. CD80 and CD86 were induced in Csf2−/− uterine CD11c+ cells by culture with GM-CSF. Substantially reduced ability to activate both CD4+ and CD8+ T cells in vivo was evident after delivery of OVA Ag by mating with Act-mOVA males or transcervical administration of OVA peptides. This study shows that GM-CSF regulates the efficiency with which uterine DCs and macrophages activate T cells, and it is essential for optimal MHC class II- and class I-mediated indirect presentation of reproductive Ags. Insufficient GM-CSF may impair generation of T cell-mediated immune tolerance at the outset of pregnancy and may contribute to the altered DC profile and dysregulated T cell tolerance evident in infertility, miscarriage, and preecl sia.
Publisher: Oxford University Press (OUP)
Date: 09-2015
DOI: 10.1095/BIOLREPROD.114.125740
Abstract: Seminal fluid interacts with epithelial cells lining the female reproductive tract to induce expression of proinflammatory cytokines and chemokines, initiating immune tolerance mechanisms to facilitate pregnancy. TGFB cytokines are key signaling agents in seminal plasma but do not fully account for the female response to seminal fluid. We hypothesized that additional molecular pathways are utilized in seminal fluid signaling. Affymetrix microarray was employed to compare gene expression in the endometrium of mice 8 h after mating with either intact males or seminal fluid deficient (SVX/VAS) males. Bioinformatics analysis revealed TLR4 signaling as a strongly predicted upstream regulator activated by the differentially expressed genes and implicated TGFB signaling as a second key pathway. Quantitative PCR and microbead data confirmed that seminal fluid induces endometrial synthesis of several TLR4-regulated cytokines and chemokines, including CSF3, CXCL1, CXCL2, IL1A, IL6, LIF, and TNF. In primary uterine epithelial cells, CSF3, CXCL1, and CXCL2 were strongly induced by the TLR4 ligand LPS but suppressed by TGFB, while IL1A, TNF, and CSF2 were induced by both ligands. TLR4 was confirmed as essential for the full endometrial cytokine response using mice with a null mutation in Tlr4, where seminal fluid failed to induce endometrial Csf3, Cxcl2, Il6, and Tnf expression. This study provides evidence that TLR4 contributes to seminal fluid modulation of the periconception immune environment. Activation of TLR4 signaling by microbial or endogenous components of seminal fluid is thus implicated as a key element of the female tract response to seminal fluid at the outset of pregnancy in mice.
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.JRI.2014.07.002
Abstract: The mammary gland is a unique organ that undergoes hormone-driven developmental changes over the course of the ovarian cycle during adult life. Macrophages play a role in regulating cellular turnover in the mammary gland and may affect cancer susceptibility. However, the immune microenvironment that regulates macrophage function has not been described. Hormonal regulation of the cytokine microenvironment across the ovarian cycle was explored using microbead multiplex assay for 15 cytokines in mammary glands from C57Bl/6 mice at different stages of the oestrous cycle, and in ovariectomised mice administered oestradiol and progesterone. The cytokines that were found to fluctuate over the course of the oestrous cycle were colony-stimulating factor (CSF)1, CSF2, interferon gamma (IFNG) and tumour necrosis factor alpha (TNFA), all of which were significantly elevated at oestrus compared with other phases. The concentration of serum progesterone during the oestrus phase negatively correlated with the abundance of cytokines CSF3, IL12p40, IFNG and leukaemia inhibitory factor (LIF). In ovariectomised mice, exogenous oestradiol administration increased mammary gland CSF1, CSF2, IFNG and LIF, compared with ovariectomised control mice. Progesterone administration together with oestradiol resulted in reduced CSF1, CSF3 and IFNG compared with oestradiol administration alone. This study suggests that the cytokine microenvironment in the mammary gland at the oestrus phase of the ovarian cycle is relatively pro-inflammatory compared with other stages of the cycle, and that the oestradiol-induced cytokine microenvironment is significantly attenuated by progesterone. A continuously fluctuating cytokine microenvironment in the mammary gland presumably regulates the phenotypes of resident leukocytes and may affect mammary gland cancer susceptibility.
Publisher: Oxford University Press (OUP)
Date: 02-1993
DOI: 10.1095/BIOLREPROD48.2.277
Abstract: The ovulatory process has been compared with inflammation because several classical inflammatory mediators appear to participate in this process. One component of the inflammatory reaction is the migration of leukocytes to the site of inflammation and the subsequent activation of these cells. We have reported recently that perfusion of leukocytes into the rat ovary in vitro enhances the number of LH-induced ovulations, which suggests an active role of leukocytes in ovulation. In the present study we characterize immunohistochemically the distribution of macrophages, T lymphocytes, and granulocytes in the ovaries of untreated immature rats and of eCG-hCG-primed rats killed prior to hCG injection, at ovulation, and at 33-36 h post-ovulation. Macrophages, identified with monoclonal antibodies ED1 and ED2, were the major leukocyte population and were found primarily in the medullary region surrounding the blood vessels. The density of the cells in this region increased continuously during development to sexual maturity and until after ovulation. Macrophages were also present in the thecal layer of the preovulatory follicles, and the numbers of these cells increased about 5-fold in this area in ovulating follicles (12 h after hCG) compared to preovulatory follicles (before hCG). A portion of macrophages in both areas expressed major histocompatibility complex (MHC) class II antigens (OX6+) these cells were present mostly in the medullary region, with no apparent change in density during the periovulatory period. Neutrophilic granulocytes comprised a lesser proportion of the total leukocyte population in the medullary region but were abundant in the thecal layer. The density of neutrophils increased 3-fold in the medullary region and 8-fold in the thecal region in ovulatory compared to preovulatory follicles. T lymphocytes (OX52+) were evenly distributed at relatively low density in the medulla and the stroma of the cortex. Most T lymphocytes expressed the CD8 antigen (OX8+) and hence were of the MHC class I-restricted phenotype. Few T lymphocytes were present in the thecal layer. In summary, macrophages, neutrophilic granulocytes, and T lymphocytes are present in the ovary at ovulation. There is a selective increase in the numbers of macrophages and neutrophilic granulocytes in the medullary region and in the thecal layer as the ovulatory period progresses, indicating that these cells may actively be involved in the tissue remodeling occurring at ovulation.
Publisher: Elsevier BV
Date: 12-2009
DOI: 10.1016/J.JRI.2009.08.003
Abstract: A state of active tolerance mediated by T regulatory (Treg) cells must be functional from the time of embryo implantation to prevent the conceptus from maternal immune attack. Male seminal fluid and ovarian steroid hormones are implicated in regulating the size and suppressive function of the Treg cell pool during the peri-implantation phase of early pregnancy. Evidence that antigens and cytokine signals in seminal fluid regulate the maternal immune response includes the following: (1) the Treg cell-inducing cytokine TGFbeta and male alloantigens are present in seminal fluid (2) seminal fluid delivery at coitus is sufficient to induce a state of active immune tolerance to paternal alloantigen, even in the absence of conceptus tissue (3) female dendritic cells can cross-present seminal fluid antigens to activate both CD8(+) and CD4(+) T cells, and (4) mating events deficient in either sperm or seminal plasma result in diminished CD4(+) CD25(+) Foxp3(+) Treg cell populations at the time of embryo implantation. Ongoing studies indicate that the cytokine environment during priming to male seminal fluid antigens influences the phenotype of responding T cells, and impacts fetal survival in later gestation. Collectively, these observations implicate factors in the peri-conceptual environment of both male and female origin as important determinants of maternal immune tolerance. Defining the mechanisms controlling tolerance induction will be helpful for developing new therapies for immune-mediated pathologies of pregnancy such as miscarriage and pre-ecl sia.
Publisher: Oxford University Press (OUP)
Date: 06-2004
Publisher: Elsevier BV
Date: 11-1999
DOI: 10.1016/S0165-0378(99)00022-4
Abstract: The abundant macrophage populations present in the endometrium are implicated in the tissue remodelling events and immunological changes necessary for pregnancy. Using two regimens of restricted nutrition (95 and 88% of ad libitum intake for 19 days), we have shown that moderately reduced food consumption can dramatically alter the number of endometrial macrophages and their immunoaccessory function in mice. Restricted nutrition also interfered with the estrous cycle, but the effects on endometrial macrophages were more extensive and qualitatively different than could be explained by diminished ovarian steroid hormone activity. Significantly less F4/80+ and Ia+ cells were found in the endometrium of food restricted mice than in ad libitum mice at the same estrous cycle stage. In the more severely restricted mice the losses were even greater than those seen after ovariectomy. In ad libitum fed animals, uterine but not peritoneal macrophages showed an ovarian hormone-dependent inhibitory phenotype in a splenocyte mitogenesis assay. Macrophages derived from both locations exhibited greater immunostimulatory activity following restricted nutrition. We conclude that endometrial macrophage populations are influenced by nutritional status and this may be mediated through both steroid hormone-dependent and -independent mechanisms. Nutritionally induced aberrations in the number or behaviour of endometrial macrophages during the estrous cycle or in early pregnancy could have important implications for the quality of the pre- and peri-implantation environment and the maternal immune response to pregnancy.
Publisher: American Society for Clinical Investigation
Date: 22-03-2023
Publisher: Oxford University Press (OUP)
Date: 02-2012
DOI: 10.1095/BIOLREPROD.111.098301
Abstract: The discovery of dynamic populations of regulatory T cells in the corpus luteum opens new possibilities for immune regulation of early pregnancy.
Publisher: Oxford University Press (OUP)
Date: 27-03-2018
Abstract: Seminal fluid interacts with the female reproductive tract to initiate a permissive immune response that facilitates embryo implantation and pregnancy success. The immune-regulatory cytokine interferon-γ (IFNG), which can be elevated in seminal plasma, is associated with reduced fertility. Here, we investigated how IFNG influences the female immune response to seminal fluid. In human Ect1 cervical epithelial cells, IFNG added at physiologically relevant concentrations substantially impaired seminal plasma-induced synthesis of key cytokines colony-stimulating factor 2 (CSF2) and interleukin-6 (IL6). Seminal fluid-induced CSF2 synthesis was also suppressed in the uterus of mice in vivo, when IFNG was delivered transcervically 12 h after mating. Transforming growth factor B1 (TGFB1) is the major seminal fluid signaling factor which elicits CSF2 induction, and IFNG exhibited potent dose-dependent suppression of CSF2 synthesis induced by TGFB1 in murine uterine epithelial cells in vitro. Similarly, IFNG suppressed TGFB1-mediated CSF2 induction in Ect1 cells and human primary cervical epithelial cells however, IL6 regulation by IFNG was independent of TGFB1. Quantitative PCR confirmed that CSF2 regulation by IFNG in Ect1 cells occurs at the gene transcription level, secondary to IFNG suppression of TGFBR2 encoding TGFB receptor 2. Conversely, TGFB1 suppressed IFNG receptor 1 and 2 genes IFNGR1 and IFNGR2. These data identify IFNG as a potent inhibitor of the TGFB-mediated seminal fluid interaction with relevant reproductive tract epithelia in mice and human. These findings raise the prospect that IFNG in the male partner's seminal fluid impairs immune adaptation for pregnancy following coitus in women.
Publisher: Oxford University Press (OUP)
Date: 11-03-2009
Publisher: Elsevier BV
Date: 03-2000
DOI: 10.1016/S0165-0378(99)00060-1
Abstract: Factors in seminal plasma elicit a surge of GM-CSF expression in uterine epithelial cells after mating in mice. This study investigates the nature of the endometrial cell populations targeted by epithelial GM-CSF. In quantitative RT-PCR studies, expression of the alpha-subunit of the GM-CSF receptor (GM-CSF-R) parallelled GM-CSF expression, being maximal during the 48 h period after mating and declining thereafter. Expression of mRNA encoding beta-common chain (AIC2B) also increased after mating and remained high until the time of embryo implantation on day 4 of pregnancy. Cells expressing GM-CSF receptors were identified in sections of uterus on the day after mating using 125I-GM-CSF, and were located predominantly in the endometrial stroma subjacent to the luminal epithelium, co-localising with abundant populations of myeloid leukocytes. Cells expressing GM-CSF receptor were identified as macrophages, granulocytes and putative dendritic cells by flow cytometric analysis using lineage and receptor subunit specific antibodies. Recombinant GM-CSF injected into the uterine lumen of ovariectomised mice was found to elicit a dose-dependant accumulation of macrophages and granulocytes in the endometrium, in a pattern of distribution comparable to that seen in uteri after natural mating. Together, these data indicate a role for epithelial cell-derived GM-CSF in mediating the recruitment and potentially in modifying the behaviour of uterine leukocytes during the post-mating inflammatory response in mice.
Publisher: Oxford University Press (OUP)
Date: 1996
DOI: 10.1095/BIOLREPROD54.1.183
Abstract: Uterine epithelial cells have been shown by in vitro studies to be a potent source of the inflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF), and the luminal and glandular epithelium has been confirmed as the predominant site of GM-CSF expression in the intact endometrium by in situ hybridization. To examine the role of ovarian steroid hormones in GM-CSF synthesis, GM-CSF bioactivity has been measured in the supernatants of short-term primary cultures of endometrial cells prepared from mice in which steroid levels were perturbed by ovariectomy and steroid replacement or by steroid antagonists. GM-CSF production was found to fluctuate in cells harvested at different times during the estrous cycle, peaking at estrus. Endometrial cells derived from ovariectomized mice produced 25-fold less GM-CSF than did cells from estrous mice, and production was increased if ovariectomized mice were pretreated with estrogen, but not progesterone, 3 h or more before harvest. This estrogen-induced increase was inhibited by coadministration of progesterone or by induction of a decidual response and was blocked by the estrogen antagonist ZK 119,010. By contrast, pretreatment of mice with the anti-progestin RU486 significantly elevated GM-CSF output in cells from ovariectomized mice given estrogen and progesterone in combination and antagonized the inhibition of GM-CSF release seen in cells harvested from mice treated with hCG. These studies demonstrate that GM-CSF synthesis and/or release by uterine epithelial cells is stimulated by estrogen, with progesterone having a moderate inhibitory effect. Analysis of GM-CSF mRNA expression in uterine epithelial cell cultures and in intact uteri from steroid hormone-treated ovariectomized mice by quantitative reverse transcription-polymerase chain reaction indicated that the effects of estrogen and progesterone on GM-CSF release are mediated at least in part at the transcriptional level. These findings implicate GM-CSF as a local mediator of steroid-driven remodeling events in the cycling and preimplantation endometrium, possibly acting through the recruitment and behavioral regulation of granulocytes and macrophages.
Publisher: Massachusetts Medical Society
Date: 14-03-2019
Publisher: Oxford University Press (OUP)
Date: 11-2002
DOI: 10.1093/HUMREP/17.11.2783
Abstract: Does the manipulation of gametes and embryos as practised in human IVF invoke perturbations in fetal and neonatal phenotype? There is increasing evidence that the answer is 'yes', although the degree of perturbation may be less acute than observed in other species. However, the long-term consequences are not known, and may prove to be considerable. There is now a substantial body of evidence from animal models suggesting that assisted reproductive technologies (ART) are associated with altered outcomes in fetal and neonatal development. Epigenetic modification of gene expression is an attractive hypothesis that accounts for these differences and is one of a number of causal pathways that may be activated by cellular stress invoked during manipulation. Here we widen the debate to propose that environment-induced cellular stress also acts to modify fetal and placental gene expression, potentially also contributing to phenotype skewing after ART.
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.AJOG.2016.08.027
Abstract: The ability to provide safe and effective pharmacotherapy during obstetric complications, such as preterm labor or postpartum hemorrhage, is h ered by the systemic toxicity of therapeutic agents leading to adverse side effects in the mother and fetus. Development of novel strategies to target tocolytic and uterotonic agents specifically to uterine myocytes would improve therapeutic efficacy while minimizing the risk of side effects. Ligand-targeted liposomes have emerged as a reliable and versatile platform for targeted drug delivery to specific cell types, tissues or organs. Our objective was to develop a targeted drug delivery system for the uterus utilizing an immunoliposome platform targeting the oxytocin receptor. We conjugated liposomes to an antibody that recognizes an extracellular domain of the oxytocin receptor. We then examined the ability of oxytocin receptor-targeted liposomes to deliver contraction-blocking (nifedipine, salbutamol and rolipram) or contraction-enhancing (dofetilide) agents to strips of spontaneously contracting myometrial tissue in vitro (human and mouse). We evaluated the ability of oxytocin receptor-targeted liposomes to localize to uterine tissue in vivo, and assessed if targeted liposomes loaded with indomethacin were capable of preventing lipopolysaccharide-induced preterm birth in mice. Oxytocin receptor-targeted liposomes loaded with nifedipine, salbutamol or rolipram consistently abolished human myometrial contractions in vitro, while oxytocin receptor-targeted liposomes loaded with dofetilide increased contraction duration. Nontargeted control liposomes loaded with these agents had no effect. Similar results were observed in mouse uterine strips. Following in vivo administration to pregnant mice, oxytocin receptor-targeted liposomes localized specifically to the uterine horns and mammary tissue. Targeting increased localization to the uterus 7-fold. Localization was not detected in the maternal brain or fetus. Targeted and nontargeted liposomes also localized to the liver. Oxytocin receptor-targeted liposomes loaded with indomethacin were effective in reducing rates of preterm birth in mice, whereas nontargeted liposomes loaded with indomethacin had no effect. Our results demonstrate that oxytocin receptor-targeted liposomes can be used to either inhibit or enhance human uterine contractions in vitro. In vivo, the liposomes localized to the uterine tissue of pregnant mice and were effective in delivering agents for the prevention of inflammation-induced preterm labor. The potential clinical advantage of targeted liposomal drug delivery to the myometrium is reduced dose and reduced toxicity to both mother and fetus.
Publisher: Wiley
Date: 24-01-2016
DOI: 10.1111/AJI.12490
Abstract: To support embryo implantation, the female reproductive tract must provide a tolerogenic immune environment. Seminal fluid contact at conception contributes to activating the endometrial gene expression and immune cell changes required for robust implantation, influencing not only the quality of the ensuing pregnancy but also the health of offspring. miRNAs are small non-coding RNAs that play important regulatory roles in biological processes, including regulation of the immune environment. miRNAs are known to contribute to gene regulation in pregnancy and are altered in pregnancy pathologies. Recent studies indicate that miRNAs participate in establishing immune tolerance at conception, and may contribute to the regulatory effects of seminal fluid in generating tolerogenic dendritic cells and T regulatory cells. This review highlights those miRNAs implicated in programming immune cells that are critical during the peri-conception period and explores how seminal fluid may regulate female tract miRNA expression following coitus.
Publisher: Oxford University Press (OUP)
Date: 1994
DOI: 10.1095/BIOLREPROD50.1.88
Abstract: To examine the production of cytokines by the ovary during ovulation, ovaries were obtained from immature rats and from eCG/hCG-primed immature rats at different stages of the ovulatory process (before hCG injection, 10 h after hCG, and 20 h after hCG) and were perfused in vitro for 5 h. Large quantities of interleukin (IL)-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) bioactivity and smaller amounts of tumor necrosis factor-alpha (TNF alpha) and IL-1 bioactivity were found in the perfusate. IL-2 and IL-3 were not detectable in the perfusion media. The GM-CSF content was significantly higher in the perfusate of ovulating ovaries (obtained 10 h after hCG) compared to the earlier stages. Studies on preovulatory ovaries (prior to hCG injection) revealed that GM-CSF release was not influenced by LH, but was markedly increased when recombinant human IL-1 beta (4 ng/ml) was added to the perfusion medium. IL-6 was released in similar amounts from ovaries at all stages. The identity of bioactive GM-CSF was confirmed by neutralization with a specific polyclonal antibody against murine GM-CSF. Size-exclusion chromatography of perfusion medium revealed peaks of GM-CSF and IL-6 bioactivity at approximate molecular masses of 21-23 kDa and 24-25 kDa, respectively. This study demonstrates that the rat ovary produces IL-6, GM-CSF, TNF alpha, and IL-1 prior to and during the ovulatory process and that there are temporal fluctuations in GM-CSF release with a peak in output at ovulation.
Publisher: Oxford University Press (OUP)
Date: 04-2000
DOI: 10.1095/BIOLREPROD62.4.1059
Abstract: To investigate the role of the ovarian macrophage population in ovulation, we examined the effect of depleting this population using liposome-encapsulated clodronate. Clodronate liposomes, saline liposomes, or saline alone was injected under the ovarian bursa in gonadotropin-primed adult mice, either 84 h (Day -3) or 36 h (Day -1) before ovulation. Ovulation rates were determined by counting the number of oocytes released. The numbers of graafian follicles and corpora lutea were also counted immediately before and after ovulation. Macrophage distribution within the theca and stroma of preovulatory ovaries was examined by immunohistochemistry with specific monoclonal antibodies to the macrophage antigens macrosialin, major histocompatability complex class II (Ia), and F4/80. Injection of clodronate liposomes on Day -1 did not affect ovulation rates, whereas administration on Day -3 caused a significant reduction in ovulation rate (mean oocytes ovulated = 5. 25 +/- 0.6 from clodronate liposome-treated ovaries and 9.13 +/- 0.9 from saline-treated ovaries, respectively, P < 0.05). The numbers of macrosialin-positive macrophages present in the theca at ovulation were reduced by treatment with clodronate liposomes on Day -1, and treatment on Day -3 reduced the numbers of Ia-positive and macrosialin-positive macrophages present in the theca. When the subsequent ovarian cycles were examined by vaginal smearing, the metestrous-2/diestrous stage was found to be extended in clodronate liposome-treated animals (7.5 +/- 1.3 days vs. 3.4 +/- 0.4 days for saline liposome-treated animals, P < 0.05). These results suggest that thecal macrophages may be involved in the regulation of follicular growth and rupture, as well as being important for the normal progression of the estrous cycle.
Publisher: CSIRO Publishing
Date: 1992
DOI: 10.1071/RD9920435
Abstract: Granulocyte-macrophage colony stimulating factor (GM-CSF) is one of a number of lympho-haemapoietic cytokines, including CSF-1, interleukin-6 (IL-6) and leukaemia inhibitory factor (LIF) now known to be synthesized by epithelial cells in the murine uterus. GM-CSF synthesis is regulated primarily by the ovarian steroid hormone oestrogen, but is also subject to modulation by factors including a seminal component of seminal vesicle origin which stimulates a 20-fold increase in luminal fluid content at mating, and bacterial lipopolysaccharide (LPS) and the T-lymphocyte and natural killer (NK) cell product interferon-gamma (IFN gamma). In the non-pregnant mouse GM-CSF synthesis peaks at oestrus. Synthesis is maintained at comparable or moderately higher levels during the preimplantation period of pregnancy and in the non-decidualized endometrium during mid gestation. An embryotrophic activity is suggested by studies in vitro that indicate that GM-CSF stimulates attachment and outgrowth of blastocysts. It is postulated that GM-CSF is of major importance to the physiology of pregnancy through its role as a component of a local cytokine circuit acting to recruit and regulate function of endometrial leukocytes, and by its action as interlocutor and important effector arm in embryo-maternal interactions during gestation.
Publisher: Oxford University Press (OUP)
Date: 1996
Abstract: In recent years it has become evident that a leukocyte-cytokine network contributes to the paracrine regulation of ovarian function. The objectives of this study were to examine the presence of a potent lympho-haemopoietic cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF), in tissues and fluids from human ovaries. In a prospective study, follicular fluid and plasma were collected from naturally cycling women and women undergoing hyperstimulation for in-vitro fertilization (IVF). Granulosa-lutein cells were collected at the time of oocyte recovery for IVF and corpora lutea were collected at the time of hysterectomy for non-ovarian reasons. Culture supernatants from ovarian cell and tissue cultures were harvested on completion of a 48 h incubation. Immunoactive GM-CSF was measured by enzyme-linked immunosorbent assay, and was found to be present at statistically significantly higher levels in follicular fluid (8.9 +/- 0.7 pg/ml) and plasma (11.3 +/- 0.8 pg/ml) of women undergoing hyperstimulation compared to follicular fluid (5.3 +/- 0.3 pg/ml) and plasma (7.1 +/- 0.5 pg/ml) from naturally cycling women. Immunoactive GM-CSF was also detected in culture supernatants of granulosa-lutein cells (47.6 pg/10(5) cells), early luteal phase corpora lutea (0.52 pg/microgram DNA) and mid-luteal phase corpora lutea (0.98 pg/microgram DNA). Furthermore, transcripts for GM-CSF, and both the alpha and beta subunits of the GM-CSF receptor, were detected by reverse transcription polymerase chain reaction (RT-PCR) in granulosa-lutein cell culture preparations and corpora lutea collected during the early, mid- and late luteal phase of the menstrual cycle. These results show that GM-CSF is expressed and secreted by cells within the human ovary, and, together with the finding of expression of mRNA for GM-CSF receptor, suggest a role for GM-CSF in the local regulation of ovarian events.
Publisher: Frontiers Media SA
Date: 04-10-2021
Publisher: Bioscientifica
Date: 07-1996
Abstract: Mating evokes a characteristic pattern of molecular and cellular events in the rodent reproductive tract, including an infiltration of the endometrial stroma and uterine lumen with activated macrophages and granulocytes, which closely resembles a classic inflammatory response. Previous studies in mice indicate that these cellular changes are associated with, and are largely a consequence of, an upregulated synthesis and release of granulocyte-macrophage colony-stimulating factor (GM-CSF) from the uterine epithelium in response to seminal fluid. The aim of this study was to investigate further the origin and nature of the factors present in seminal fluid that trigger the GM-CSF response. It was found that the characteristic increase in uterine expression of mRNA encoding GM-CSF and release of GM-CSF bioactivity from uterine epithelial cells into the luminal cavity seen after mating with intact or vasectomized males was no longer evident in matings with male mice from whom the seminal vesicles had been surgically removed. The extent of inflammatory leucocyte infiltration into the endometrium was also reduced the most notable effect was a complete absence of the exocytosis of neutrophils into the luminal cavity normally seen after matings with intact or vasectomized males. Bioassay of the GM-CSF output of oestrous endometrial cells after culture with crude or Sephacryl S-400 chromatographed fractions of seminal vesicle fluid showed that the GM-CSF stimulating activity was predominantly associated with protein moieties in seminal vesicle fluid of approximately 650,000 M(r) and 100,000-400,000 M(r). These data confirm the presence in seminal vesicle fluid of specific factors that initiate an inflammatory response in the uterus after mating through upregulating GM-CSF synthesis in the uterine epithelium. The significance of the cytokine release and cellular changes induced by seminal plasma for implantation of the conceptus and pregnancy outcome remain to be determined.
Publisher: Springer New York
Date: 2015
DOI: 10.1007/978-1-4939-2480-6_7
Abstract: In the physiological situation, cytokines are pivotal mediators of communication between the maternal tract and the embryo. Compelling evidence shows that cytokines emanating from the oviduct and uterus confer a sophisticated mechanism for 'fine-tuning' of embryo development, influencing a range of cellular events from cell survival and metabolism, through ision and differentiation, and potentially exerting long-term impact through epigenetic remodelling. The balance between survival agents, including GM-CSF, CSF1, LIF, HB-EGF and IGFII, against apoptosis-inducing factors such as TNFα, TRAIL and IFNg, influence the course of preimplantation development, causing embryos to develop normally, adapt to varying maternal environments, or in some cases to arrest and undergo demise. Maternal cytokine-mediated pathways help mediate the biological effects of embryo programming, embryo plasticity and adaptation, and maternal tract quality control. Thus maternal cytokines exert influence not only on fertility and pregnancy progression but on the developmental trajectory and health of offspring. Defining a clear understanding of the biology of cytokine networks influencing the embryo is essential to support optimal outcomes in natural and assisted conception.
Publisher: Wiley
Date: 17-09-2021
DOI: 10.1111/AJI.13338
Publisher: Elsevier
Date: 2018
Publisher: Elsevier BV
Date: 10-2002
DOI: 10.1016/S0165-0378(02)00015-3
Abstract: TGFbeta is a potent immune deviating agent, driving active forms of immune tolerance in peripheral tissues through effects on the induction and resolution of inflammatory responses and phenotype skewing in antigen-presenting cells and lymphocytes. The TGFbeta content of seminal plasma from human, rodent and livestock species is amongst the highest measured in biological fluids. The seminal vesicle gland is the principal source of TGFbeta in the semen of mice, where its synthesis is regulated by testosterone. At insemination, seminal TGFbeta is deposited in the female tract and is activated by acidic vaginal pH, enzymes of male or female tract origin, or through cleavage-independent processes involving conformational change after interaction with epithelial cell docking proteins. Seminal TGFbeta has been shown to be a principal stimulating agent in the post-coital inflammatory response, and is likely to be essential for induction of immune tolerance to seminal antigens. As well as preventing aberrant immunity to spermatozoa, these events are implicated in priming an appropriate female immune response to embryo implantation, since many seminal antigens are shared by the conceptus. The cascade of immunological events elicited by seminal TGFbeta may therefore explain epidemiological observations linking acute and cumulative exposure to semen with successful placental development and pregnancy outcome. Depending on whether the female tract has evolved mechanisms to discriminate seminal antigens from opportunistic pathogens, there may be a detrimental cost of seminal TGFbeta in inhibiting protective immunity to agents of sexually transmitted disease including HIV. A better understanding of the significance and role of TGFbeta in semen will facilitate development of novel therapies for immune-based infertility disorders.
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.JRI.2019.01.002
Abstract: Endometriotic lesion development involves complex interactions between endometrial tissue, the peritoneum and immune cells. Macrophages are essential in this process however their precise roles are not defined. To investigate whether infiltrating macrophages acquire functionally different phenotypes during lesion development, human endometrial tissues were grafted into immunodeficient mice expressing macrophage-specific green fluorescent protein (GFP). Although the numbers of GFP-positive macrophages were similar in lesions 4, 7, 10 and 14 days after grafting, their surface markers changed over time. Inflammatory markers MHC class II (MHC II) and iNOS were present on 36% and 41% of macrophages respectively early in lesion development at day 4, whereas abundance of tissue remodelling markers peaked later, with arginase 1 most highly expressed on 57% of macrophages at day 7 and scavenger receptor A (CD204) on 66% of macrophages at day 14. This is consistent with a transition from classical M1 macrophage activity to an alternate M2 profile, which correlates to histological hallmarks of initially acute inflammation followed by tissue remodelling during lesion development. This progressive shift in phenotype is likely to be relevant to the mechanisms by which macrophages are central players in endometriosis-like lesion development.
Publisher: Wiley
Date: 10-04-2023
DOI: 10.1111/ANDR.13424
Abstract: Seminal plasma cytokines are associated with fertility and reproductive health, but progressing their clinical utility is h ered by absence of reference data on concentration ranges of relevant cytokines in healthy men. We employed a systematic approach to assemble current evidence on the concentrations of immune regulatory cytokines present in seminal plasma (SP) of normozoospermic and/or fertile men and evaluated the impact of different platform methodologies for cytokine quantification. A systematic literature search was performed utilising PubMed, Web of Science and Scopus. Databases were searched from inception until 30th June 2022 inclusive, using combinations of keywords pertaining to seminal fluid and cytokines, and was restricted to human participants. Original data with values reported as concentration of specific cytokines in SP of men clearly defined as fertile or normozoospermic were extracted from studies written in English. A total of 3769 publications were initially identified, of which 118 fulfilled the eligibility criteria for inclusion. A total of 51 in idual cytokines are detectable in SP of healthy men. The number of studies reporting on each cytokine range from 1 to . The reported concentrations for many cytokines linked with fertility status, including IL6, CXCL8/IL8, and TNFA, are highly variable between published studies. This is associated with the different immunoassay methodologies utilised and may be exacerbated by a lack of validation of assays to ensure suitability for SP assessment. Due to the large variation between studies, accurate reference ranges for healthy men cannot be determined from the published data. The concentrations of cytokines and chemokines detected in SP is inconsistent and highly variable between studies and cohorts, limiting current capacity to define reference ranges for cytokine concentrations in fertile men. The lack of standardisation in methods used to process and store SP, and variation in platforms used to evaluate cytokine abundance, are factors contributing to the observed heterogeneity. To progress the clinical utility of SP cytokine analysis will require standardisation and validation of methodologies so that reference ranges for healthy fertile men can be defined.
Publisher: S. Karger AG
Date: 2016
DOI: 10.1159/000443961
Abstract: b i Background: /i /b Around 30-40% of the world's population will experience allergy, the most common and earliest-onset noncommunicable disease. With a steady rise in the incidence of allergic disease over recent decades, up to 18% of children will suffer a respiratory, food or skin allergy before their 18th birthday. There is compelling evidence that the risk of developing allergy is influenced by early life events and particularly in utero exposures. b i Methods: /i /b A comprehensive literature review was undertaken which outlines prenatal risk factors and potential mechanisms underlying the development of allergy in childhood. b i Results: /i /b Exposures including maternal cigarette smoking, preterm birth and Caesarean delivery are implicated in predisposing infants to the later development of allergy. In contrast, restricted growth in utero, a healthy maternal diet and a larger family size are protective, but the mechanisms here are unclear and require further investigation. b i Conclusion: /i /b To ameliorate the allergy pandemic in young children, we must define prenatal mechanisms that alter the programming of the fetal immune system and also identify specific targets for antenatal interventions.
Publisher: Elsevier BV
Date: 11-1996
DOI: 10.1016/S0165-0378(96)88352-5
Abstract: Macrophages are ubiquitous cells with an impressive range of functions. These include phagocytosis and coordination of the initiation and effector phases of immune responses, as well as production of bioactive proteins and lipids that profoundly influence cell growth, differentiation and function. Macrophages are highly in idualized in tissues, where their activities are a reflection of targeting by systemic and local environmental signals. This review focuses on recent studies where uterine macrophage population densities and distribution have been mapped, chemotaxis, differentiation and activation have been investigated and production of potent effector molecules has been explored. Evidence supporting a major role for female sex steroid hormones and the uterine growth factors they control in governing these features of uterine macrophages is presented.
Publisher: Begell House
Date: 1994
DOI: 10.1615/CRITREVIMMUNOL.V14.I3-4.30
Abstract: Lymphohemopoietic cytokines are now recognized to be central participants in the cellular communication events underlying the complex and dynamic remodeling processes required to accommodate the semiallogeneic conceptus during mammalian reproduction. Cytokines are identified to be particular importance in mediating communications between the conceptus and maternal cells, particularly the uterine epithelium and infiltrating leukocytes, both prior to implantation and as the placenta develops. In this review we summarize recent experimental data concerning the synthesis of various cytokines in uterine and conceptus-derived tissues and highlight current hypotheses for their roles in establishing and maintaining successful pregnancy. It is concluded that complex and finely balanced cytokine networks underpin precise regulatory mechanisms controlling the rate and degree of conceptus development and invasion into maternal tissues.
Publisher: Georg Thieme Verlag KG
Date: 09-09-2015
Abstract: To study, in women with a spontaneous preterm birth (sPTB) in the first pregnancy, the effect of fetal sex in that first pregnancy on the recurrent sPTB risk. A nationwide retrospective cohort study (data from National Perinatal Registry) on all women with two sequential singleton pregnancies (1999-2009) with the first delivery ending in sPTB <37 weeks. We used logistic regression analysis to study the association between fetal gender in the first pregnancy and the risk of recurrent sPTB. We repeated the analysis for sPTB < 32 weeks. The overall incidence of sPTB <37 weeks in the first pregnancy was 4.5% (15,351/343,853). Among those 15,351 women, the risk of recurrent sPTB <37 weeks was increased when the first fetus was female compared when that fetus was male (15.8 vs. 15.2% adjusted odds ratio [aOR] 1.2 95% confidence interval [CI] 1.05-1.3). A similar effect was seen for sPTB <32weeks (8.2 vs. 5.9% aOR 4.5 95% CI 1.5-13). Women who suffer sPTB of a female fetus have an increased risk of recurrent sPTB compared with women who suffer sPTB of a male fetus. This information provides proof for the hypothesis that sPTB is due to an independent maternal and fetal factor.
Publisher: Oxford University Press (OUP)
Date: 08-2011
DOI: 10.1095/BIOLREPROD.110.088591
Abstract: Regulatory T (Treg) cells facilitate maternal immune tolerance of the semiallogeneic conceptus in early pregnancy, but the origin and regulation of these cells at embryo implantation is unclear. During the preimplantation period, factors in the seminal fluid delivered at coitus cause expansion of a CD4(+)CD25(+) putative Treg cell population in the para-aortic lymph nodes draining the uterus. Using flow cytometry, immunohistochemistry, and real-time quantitative PCR (qPCR) for the signature Treg cell transcription factor FOXP3, we confirmed the identity of the expanded lymph node population as FOXP3(+) Treg cells and showed that this is accompanied by a comparable increase in the uterus of FOXP3(+) Treg cells and expression of Foxp3 mRNA by Day 3.5 postcoitum. Seminal plasma was necessary for uterine Treg cell accumulation, as mating with seminal vesicle-deficient males failed to elicit an increase in uterine Treg cells. Furthermore seminal fluid induced expression of mRNA encoding the Treg chemokine CCL19 (MIP3beta), which acts through the CCR7 receptor to regulate Treg cell recruitment and retention in peripheral tissues. Glandular and luminal epithelial cells were identified as the major cellular origins of uterine CCL19, and exposure to both seminal plasma and sperm was required for maximum expression. Together, these results indicate that Treg cells accumulate in the uterus prior to embryo implantation and that seminal fluid is a key regulator of the uterine Treg cell population, operating by both increasing the pool of available Treg cells and promoting their CCL19-mediated recruitment from the circulation into the implantation site.
Publisher: American Association for the Advancement of Science (AAAS)
Date: 03-2013
Abstract: Type I interferons (IFNs) are critical cytokines involved in host defense against pathogens, particularly viruses. IFN-ɛ is an IFN-like gene encoded within the type I IFN locus in mice and humans whose function has not been characterized. Fung et al. (p. 1088 ) created mice with a genetic deletion in Ifn -ɛ and found that, like other type I IFNs, IFN-ɛ signals through the IFN-α receptors 1 and 2. However, unlike these other cytokines, which are primarily expressed by immune cells and are induced upon immune cell triggering, IFN-ɛ was expressed exclusively by epithelial cells of the female reproductive tract in both mice and humans and its expression was hormonally regulated. IFN-ɛ–deficient mice were more susceptible to infection with herpes simplex virus 2 and Chlamydia muridarum , two common sexually transmitted pathogens.
Publisher: The American Association of Immunologists
Date: 03-2012
Abstract: In mice, seminal fluid elicits an inflammation-like response in the female genital tract that activates immune adaptations to advance the likelihood of conception and pregnancy. In this study, we examined whether similar changes in leukocyte and cytokine parameters occur in the human cervix in response to the male partner’s seminal fluid. After a period of abstinence in proven-fertile women, duplicate sets of biopsies were taken from the ectocervix in the periovulatory period and again 48 h later, 12 h after unprotected vaginal coitus, vaginal coitus with use of a condom, or no coitus. A substantial influx of CD45+ cells mainly comprising CD14+ macrophages and CD1a+ dendritic cells expressing CD11a and MHC class II was evident in both the stratified epithelium and deeper stromal tissue after coitus. CD3+CD8+CD45RO+ T cells were also abundant and increased after coitus. Leukocyte recruitment did not occur without coitus or with condom-protected coitus. An accompanying increase in CSF2, IL6, IL8, and IL1A expression was detected by quantitative RT-PCR, and microarray analysis showed genes linked with inflammation, immune response, and related pathways are induced by seminal fluid in cervical tissues. We conclude that seminal fluid introduced at intercourse elicits expression of proinflammatory cytokines and chemokines, and a robust recruitment of macrophages, dendritic cells, and memory T cells. The leukocyte and cytokine environment induced in the cervix by seminal fluid appears competent to initiate adaptations in the female immune response that promote fertility. This response is also relevant to transmission of sexually transmitted pathogens and potentially, susceptibility to cervical metaplasia.
Publisher: Wiley
Date: 08-06-2017
DOI: 10.1002/MRD.22823
Abstract: The reproductive tract environment at conception programs the developmental trajectory of the embryo, sets the course of pregnancy, and impacts offspring phenotype and health. Despite the fundamental importance of this stage of reproduction, the rate-limiting regulatory mechanisms operating locally to control fertility and fecundity are incompletely understood. Emerging studies highlight roles for microRNAs (miRNAs) in regulating reproductive and developmental processes and in modulating the quality and strength of the female immune response. Since endometrial receptivity and robust placentation require specific adaptation of the immune response, we hypothesize that miRNAs participate in establishing pregnancy through effects on key gene networks in immune cells. Our recent studies investigated miRNAs that are induced in the peri-conception environment, focusing on miRNAs that have immune-regulatory roles-particularly miR-223, miR-155, and miR-146a. Genetic mouse models deficient in in idual miRNAs are proving informative in defining roles for these miRNAs in the generation and stabilization of regulatory T cells (Treg cells) that confer adaptive immune tolerance. Overlapping and redundant functions between miRNAs that target multiple genes, combined with multiple miRNAs targeting in idual genes, indicate complex and sensitive regulatory networks. Although to date most data on miRNA regulation of reproductive events are from mice, conserved functions of miRNAs across species imply similar biological pathways operate in all mammals. Understanding the regulation and roles of miRNAs in the peri-conception immune response will advance our knowledge of how environmental determinants act at conception, and could have practical applications for animal breeding as well as human fertility.
Publisher: Oxford University Press (OUP)
Date: 05-1998
DOI: 10.1095/BIOLREPROD58.5.1217
Abstract: Mating in rodents evokes an inflammatory-like reaction within the uterine endometrium, characterized by extensive infiltration and activation of macrophages, dendritic cells, and granulocytes. This response is initiated when seminal vesicle gland-derived factors in the ejaculate stimulate uterine epithelial cells to release proinflammatory cytokines including granulocyte-macrophage colony-stimulating factor (GM-CSF). Experiments in which seminal vesicle secretions were fractionated by Sephacryl S-400 chromatography and assayed in vitro for GM-CSF-stimulating activity revealed that the seminal moiety coeluted with transforming growth factor beta1 (TGFbeta1) in the 150-440-kDa range and was neutralized by anti-TGFbeta1 antibodies. Comparable amounts of recombinant TGFbeta1 stimulated GM-CSF release in cultures of uterine epithelial cells from estrous mice and, when instilled into the uterine lumen, caused an increase in GM-CSF content and an infiltration of leukocytes into the endometrium similar to the postmating response. These results show that seminal vesicular fluid contains TGFbeta1 at levels sufficient to be the primary causative agent in the postmating inflammatory cascade through induction of GM-CSF synthesis by uterine epithelial cells. Seminal TGFbeta1 is thus implicated as a key factor in initiation of the remodeling events and immunological changes that occur in the uterus during the preimplantation period of pregnancy.
Publisher: Bioscientifica
Date: 11-2000
Abstract: Granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine secreted by lymphohaemopoietic and other cell lineages, is known to influence ovarian cyclicity and embryo development. The aim of this study was to examine the effect of GM-CSF on ovarian follicular cell function using GM-CSF-deficient (GM -/-) mice. Immature GM -/- and GM +/+ mice were stimulated with eCG, and cumulus-oocyte complexes and mural granulosa cells were collected 48 h later. Expression of GM-CSF receptor (GM-CSFR) alpha and beta mRNA subunits by cumulus-oocyte complexes and mural granulosa cells was examined using RT-PCR. Cumulus-oocyte complexes from both genotypes were found to express mRNA for the GM-CSFRalpha-subunit only, while the mural granulosa cells expressed both the alpha and beta receptor subunits. Cumulus-oocyte complexes recovered from GM -/- mice had approximately twice the number of cumulus cells per cumulus-oocyte complex than did those of GM +/+ mice (P < 0.05), even though the growth-promoting activity of denuded GM -/- oocytes was found to be equivalent to that of wild-type oocytes. GM-CSF deficiency was associated with marginally increased DNA synthesis in cumulus cells and significantly (P < 0.05) lower progesterone production by mural granulosa cells recovered from GM -/- compared with those recovered from GM +/+ mice. The addition of rec-mGM-CSF in vitro did not affect DNA synthesis in either cell type or progesterone production by mural granulosa cells, irrespective of GM-CSF status. There was no effect of GM-CSF deficiency on the capacity of FSH and insulin-like growth factor I to stimulate DNA synthesis in cumulus-oocyte complexes (approximately 15- and threefold, respectively) and in mural granulosa cells (approximately two- and threefold, respectively). Taken together, these data show that GM-CSF influences events associated with follicular maturation in mice. The effects of GM-CSF are not exerted directly in granulosa or cumulus cells, but appear to be mediated indirectly, perhaps through the agency of steroidogenesis-regulating secretions of local macrophage populations residing in the theca.
Publisher: Wiley
Date: 2021
DOI: 10.1002/CTI2.1328
Abstract: Intravenous infusion of Intralipid is an adjunct therapy in assisted reproduction treatment (ART) when immune‐associated infertility is suspected. Here, we evaluated the effect of Intralipid infusion on regulatory T cells (Treg cells), effector T cells and plasma cytokines in peripheral blood of women undertaking IVF. This prospective, observational pilot study assessed Intralipid infusion in 14 women exhibiting recurrent implantation failure, a clinical sign of immune‐associated infertility. Peripheral blood was collected immediately prior to and 7 days after intravenous administration of Intralipid. Plasma cytokines were measured by Luminex, and T‐cell subsets were analysed by flow cytometry. A small increase in conventional CD8 + T cells occurred after Intralipid infusion, but no change was seen in CD4 + Treg cells, or naïve, memory or effector memory T cells. Proliferation marker Ki67, transcription factors Tbet and RORγt, and markers of suppressive capacity CTLA4 and HLA‐DR were unchanged. Dimensionality‐reduction analysis using the tSNE algorithm confirmed no phenotype shift within Treg cells or other T cells. Intralipid infusion increased plasma CCL2, CCL3, CXCL8, GM‐CSF, G‐CSF, IL‐6, IL‐21, TNF and VEGF. Intralipid infusion elicited elevated pro‐inflammatory cytokines, and a minor increase in CD8 + T cells, but no change in pro‐tolerogenic Treg cells. Notwithstanding the limitation of no placebo control, the results do not support Intralipid as a candidate intervention to attenuate the Treg cell response in women undergoing ART. Future placebo‐controlled studies are needed to confirm the potential efficacy and clinical significance of Intralipid in attenuating cytokine induction and circulating CD8 + T cells.
Publisher: Elsevier BV
Date: 06-2017
Publisher: Oxford University Press (OUP)
Date: 11-2008
DOI: 10.1095/BIOLREPROD.108.067884
Abstract: Zona pellucida (ZP) glycoproteins are promising candidate antigens for use in immunocontraceptive vaccines because of their crucial role in mammalian fertilization. A single intraperitoneal immunization with recombinant murine cytomegalovirus engineered to express murine ZP3 (rMCMV-mZP3) induces permanent infertility with no evident systemic illness in female BALB/c mice. To investigate the mechanisms underpinning reproductive failure elicited by rMCMV-mZP3, ovarian parameters and reproductive function were evaluated at time points spanning 10 days to 5 wk after virus inoculation. Fertility was substantially impaired by 14 days after inoculation with rMCMV-mZP3 and was fully ablated by 21 days. Pregnancies established after inoculation but before complete infertility showed no adverse effects on fetal viability assessed at Day 17.5 post coitum (pc). Infertile mice retained estrous cycling activity and remained receptive to mating however, at Day 3.5 pc there were fewer developing embryos and corpora lutea, plasma progesterone content was reduced, and there was no evidence of excess unfertilized oocytes. Consistent with this, profound ovarian pathology was evident from 10 days after rMCMV-mZP3 inoculation, with a decline first in mature ovarian follicles and then in immature ovarian follicles and with diminished expression of genes regulating follicle development, including Nobox, Gdf9, and Gja1 (connexin43). Follicle loss was associated with mild focal oophoritis and with recruitment of inflammatory leukocytes, predominantly CD4(+) and CD8(+) T cells evident from 10 days after virus inoculation. These data indicate that vaccination with rMCMV-mZP3 causes permanent infertility in BALB/c mice principally due to induction of ovarian autoimmune pathology leading to progressive oocyte depletion and eventual ovulation failure.
Publisher: The Endocrine Society
Date: 02-2006
DOI: 10.1210/EN.2005-1189
Abstract: TGFβ1 is implicated in regulation of ovarian function and the events of early pregnancy. We have investigated the effect of null mutation in the Tgfβ1 gene on reproductive function in female mice. The reproductive capacity of TGFβ1 null mutant females was severely impaired, leading to almost complete infertility. Onset of sexual maturity was delayed, after which ovarian function was disrupted, with extended ovarian cycles, irregular ovulation, and a 40% reduction in oocytes ovulated. Serum FSH and estrogen content were normal, but TGFβ1 null mutant mice failed to display the characteristic proestrus surge in circulating LH. Ovarian hyperstimulation with exogenous gonadotropins elicited normal ovulation rates in TGFβ1 null mutant mice. After mating with wild-type stud males, serum progesterone content was reduced by 75% associated with altered ovarian expression of mRNAs encoding steroidogenic enzymes 3β-hydroxysteroid dehydrogenase-1 and P450 17 α-hydroxylase/C17–20-lyase. Embryos recovered from TGFβ1 null mutant females were developmentally arrested in the morula stage and rarely progressed to blastocysts. Attempts to rescue embryos by exogenous progesterone administration and in vitro culture were unsuccessful, and in vitro fertilization and culture experiments demonstrated that impaired development is unlikely to result from lack of maternal tract TGFβ1. We conclude that embryo arrest is due to developmental incompetence in oocytes developed in a TGFβ1-deficient follicular environment. This study demonstrates that TGFβ1 is a critical determinant of normal ovarian function, operating through regulation of LH activity and generation of oocytes competent for embryonic development and successful initiation of pregnancy.
Publisher: Frontiers Media SA
Date: 19-06-2017
Publisher: The American Association of Immunologists
Date: 15-06-2009
Abstract: The events that generate T cell-mediated immune tolerance in early pregnancy are ill-defined. To investigate the significance of seminal fluid Ags in activating maternal T cells, and define the underlying Ag presentation pathways, OVA-specific T cells were adoptively transferred to female mice inseminated by males ubiquitously expressing membrane-bound OVA. OVA-reactive CD8+ OT-I and CD4+ OT-II T cells transferred to mated recipients expressed activation markers CD25 and CD69 and proliferated vigorously in the para-aortic lymph nodes, but not in distal lymph nodes or spleen, and OT-I T cells expressed IFN-γ and IL-2. In contrast, OT-I T cells transferred later in pregnancy or up to 10 days postpartum expressed CD25 and CD69 and proliferated in all peripheral lymphoid tissues examined. OVA Ag was present predominantly in the plasma fraction of seminal fluid, and seminal plasma, but not sperm, was necessary for T cell proliferation. Female H-2Kb bone marrow-derived cells expressing TAP were essential for OT-I T cell proliferation, but responses were not elicited by OVA Ag presented by paternal MHC in seminal fluid or associated with placental cells. This study shows that at conception, seminal fluid drives activation and expansion of paternal Ag-reactive CD4+ and CD8+ T cell populations, and female APCs have an essential role in cross-presenting Ag to CD8+ T cells via a TAP-dependent pathway. Delivery of paternal Ags and immune-deviating cytokines by seminal fluid at conception may activate Ag-dependent CD4+ and CD8+ regulatory T cells mediating tolerance of pregnancy.
Publisher: Wiley
Date: 11-03-2013
DOI: 10.1111/AJI.12107
Abstract: T regulatory (Treg) cells are essential mediators of the maternal immune adaptation necessary for embryo implantation. In mice, insufficient Treg cell activity results in implantation failure, or constrains placental function and fetal growth. In women, Treg cell deficiency is linked with unexplained infertility, miscarriage, and pre-ecl sia. To devise strategies to improve Treg cell function, it is essential to define the origin of the Treg cells in gestational tissues, and the regulators that control their functional competence and recruitment. Male seminal fluid is a potent source of the Treg cell-inducing agents TGFβ and prostaglandin E, and coitus is one key factor involved in expanding the pool of inducible Treg cells that react with paternal alloantigens shared by conceptus tissues. In mice, coitus initiates a sequence of events whereby female dendritic cells cross-present seminal fluid antigens and activate T cells, which in turn circulate via the blood to be sequestered into the endometrium. Similar events may occur in the human genital tract, where seminal fluid induces immune cell changes that appear competent to prime Treg cells. Improved understanding of how seminal fluid influences Treg cells in women should ultimately assist in the development of new therapies for immune-mediated pathologies of pregnancy.
Publisher: Oxford University Press (OUP)
Date: 08-09-2009
Abstract: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is known to promote the development and survival of human and mouse preimplantation embryos however, the mechanism of action of GM-CSF in embryos is not defined. Mouse blastocysts were cultured from zygote stage in vitro with and without recombinant mouse GM-CSF (rmGM-CSF), and in vivo developed blastocysts were flushed from Csf2 null mutant and wild-type mice. The effect of GM-CSF on blastocyst expression of stress response and apoptosis genes was evaluated by microarray, qPCR and immunochemistry. Microarray analysis of the gene transcription profile showed suppression of stress response and apoptosis gene pathways in blastocysts exposed to rmGM-CSF in vitro. qPCR analysis confirmed that rmGM-CSF inhibited expression of heat shock protein (HSP) and apoptosis pathway genes Cbl, Hspa5, Hsp90aa1, Hsp90ab1 and Gas5 in in vitro blastocysts. Immunocytochemical analysis of HSP 1 (HSPA1A/1B HSP70), BAX, BCL2 and TRP53 (p53) in in vitro blastocysts showed that HSPA1A/1B and BCL2 proteins were less abundant when embryos were cultured with rmGM-CSF. BAX and TRP53 were unchanged at the protein level, but Bax mRNA expression was reduced after GM-CSF treatment. In in vivo developed blastocysts, Csf2 null mutation caused elevated expression of Hsph1 but not other stress response genes. We conclude that GM-CSF inhibits the cellular stress response and apoptosis pathways to facilitate embryo growth and survival, and the protective effects of GM-CSF are particularly evident in in vitro culture media, whereas in vivo other cytokines can partly compensate for absence of GM-CSF.
Publisher: American Physiological Society
Date: 07-2020
DOI: 10.1152/PHYSREV.00013.2018
Abstract: Seminal fluid is often assumed to have just one function in mammalian reproduction, delivering sperm to fertilize oocytes. But seminal fluid also transmits signaling agents that interact with female reproductive tissues to facilitate conception and .pregnancy. Upon seminal fluid contact, female tissues initiate a controlled inflammatory response that affects several aspects of reproductive function to ultimately maximize the chances of a male producing healthy offspring. This effect is best characterized in mice, where the female response involves several steps. Initially, seminal fluid factors cause leukocytes to infiltrate the female reproductive tract, and to selectively target and eliminate excess sperm. Other signals stimulate ovulation, induce an altered transcriptional program in female tract tissues that modulates embryo developmental programming, and initiate immune adaptations to promote receptivity to implantation and placental development. A key result is expansion of the pool of regulatory T cells that assist implantation by suppressing inflammation, mediating tolerance to male transplantation antigens, and promoting uterine vascular adaptation and placental development. Principal signaling agents in seminal fluid include prostaglandins and transforming growth factor-β. The balance of male signals affects the nature of the female response, providing a mechanism of ‟cryptic female choiceˮ that influences female reproductive investment. Male-female seminal fluid signaling is evident in all mammalian species investigated including human, and effects of seminal fluid in invertebrates indicate evolutionarily conserved mechanisms. Understanding the female response to seminal fluid will shed new light on infertility and pregnancy disorders and is critical to defining how events at conception influence offspring health.
Publisher: Wiley
Date: 21-07-2016
DOI: 10.1038/ICB.2015.63
Abstract: Interleukin-6 (IL6) is a determinant of the timing of parturition and birth in mice. We previously demonstrated that genetic IL6 deficiency delays parturition by ~24 h, and this is restored by administration of exogenous IL6. In this study, we have investigated whether IL6 influences the number or phenotypes of T cells or other leukocytes in uterine decidual tissue at the maternal-fetal interface. In late gestation, decidual leukocytes in Il6 null mutant (Il6(-/-)) mice exhibit an altered profile, characterized by reduced numbers of cells expressing the monocyte/macrophage marker F4/80 or the T-cell marker CD4, increased cells expressing the natural killer (NK) cell marker CD49b or the dendritic cell marker CD11c, but no change in cells expressing the neutrophil marker Ly6G. These changes are specific to late pregnancy, as similar differences in decidual leukocytes were not evident in mid-gestation Il6(-/-) mice. The IL6-regulated changes in decidual NK and dendritic cells appear secondary to local recruitment, as no comparable changes occurred in peripheral blood of Il6(-/-) mice. When exogenous IL6 was administered to restore normal timing of parturition, a partial reversal of the altered leukocyte profile was observed, with a 10% increase in the proportion of decidual CD4(+) T cells, a notable 60% increase in CD8(+) T cells including CD8(+)CD25(+)Foxp3(+) regulatory T cells and a 60% reduction in CD4(+)IL9(+) Th9 cells. Together these findings suggest that IL6-controlled accumulation of decidual CD4(+) T cells and CD8(+) regulatory T cells, with an associated decline in decidual Th9 cells, is instrumental for progressing parturition in mice.
Publisher: Georg Thieme Verlag KG
Date: 2007
Abstract: Prostaglandins produced by the intrauterine tissues of both mother and fetus (myometrium, decidua, placenta, chorion, and amnion) are involved with all of the physiologies of parturition (membrane rupture, cervical dilatation, myometrial contractility, placental separation, and uterine involution). For parturition to occur, however, the intrauterine tissues need to first be activated to prepare for the work of labor, then stimulated to initiate labor. Prostaglandins normally are considered to be stimulators of the physiologies of labor. This review presents evidence that one prostaglandin, PGF2alpha, and its receptor, FP, are also activators, especially of the decidua. Stimulated by cytokines, the decidual synthesis of PGF2alpha and the expression of FP lead to increased matrix metalloproteinase activity, further enhancement of cytokine activity, increased decidual oxytocin and oxytocin receptor expression, decreased progesterone responsiveness, and possibly, enhanced expression of vascular endothelial growth factor. These collective actions prepare the decidua for its role in parturition.
Publisher: Oxford University Press (OUP)
Date: 04-2001
DOI: 10.1095/BIOLREPROD64.4.1206
Abstract: Granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion from epithelial cells lining the female reproductive tract is induced during early pregnancy by ovarian steroid hormones and constituents of seminal plasma. In this study we have investigated the influence of GM-CSF on development of preimplantation mouse embryos. Blastocyst-stage embryos were found to specifically bind (125)I-GM-CSF and analysis of GM-CSF mRNA receptor expression by reverse transcriptase-polymerase chain reaction indicated expression of the low-affinity alpha subunit of the GM-CSF receptor, but not the affinity-converting beta subunit (beta(c)), or GM-CSF ligand. GM-CSF receptor mRNA was present in the fertilized oocyte and all subsequent stages of development, and in blastocysts it was expressed in both inner cell mass and trophectoderm cells. In vitro culture of eight-cell embryos in recombinant GM-CSF accelerated development of blastocysts to hatching and implantation stages, with a maximum response at a concentration of 2 ng/ml (77 pM). Blastocysts recovered from GM-CSF-null mutant (GM-/-) mice on Day 4 of natural pregnancy or after superovulation showed retarded development, with the total cell number reduced by 14% and 18%, respectively, compared with GM+/+ embryos. Blastocysts generated in vitro from two-cell GM-/- and GM+/+ embryos were larger when recombinant GM-CSF was added to the culture medium (20% and 24% increases in total cell numbers in GM+/+ and GM-/- blastocysts, respectively). Incubation of blastocysts with recombinant GM-CSF elicited a 50% increase in the uptake of the nonmetabolizable glucose analogue, 3-O-methyl glucose. In conclusion, these data indicate that GM-CSF signaling through the low-affinity GM-CSF receptor in blastocysts is associated with increased glucose uptake and enhanced proliferation and/or viability of blastomeres. Together, the findings implicate a physiological role for maternal tract-derived GM-CSF in targeting the preimplantation embryo, and suggest that defective blastocyst development contributes to compromised pregnancy outcome in GM-CSF-null mutant mice.
Publisher: Elsevier BV
Date: 07-1992
Publisher: Public Library of Science (PLoS)
Date: 10-03-2023
DOI: 10.1371/JOURNAL.PPAT.1010843
Abstract: The immunological surveillance factors controlling vulnerability of the female reproductive tract (FRT) to sexually transmitted viral infections are not well understood. Interferon-epsilon (IFNɛ) is a distinct, immunoregulatory type-I IFN that is constitutively expressed by FRT epithelium and is not induced by pathogens like other antiviral IFNs α, β and λ. We show the necessity of IFNɛ for Zika Virus (ZIKV) protection by: increased susceptibility of IFNɛ -/- mice their “rescue” by intravaginal recombinant IFNɛ treatment and blockade of protective endogenous IFNɛ by neutralising antibody. Complementary studies in human FRT cell lines showed IFNɛ had potent anti-ZIKV activity, associated with transcriptome responses similar to IFNλ but lacking the proinflammatory gene signature of IFNα. IFNɛ activated STAT1/2 pathways similar to IFNα and λ that were inhibited by ZIKV-encoded non-structural (NS) proteins, but not if IFNε exposure preceded infection. This scenario is provided by the constitutive expression of endogenous IFNε. However, the IFNɛ expression was not inhibited by ZIKV NS proteins despite their ability to antagonise the expression of IFNβ or λ. Thus, the constitutive expression of IFNɛ provides cellular resistance to viral strategies of antagonism and maximises the antiviral activity of the FRT. These results show that the unique spatiotemporal properties of IFNε provides an innate immune surveillance network in the FRT that is a significant barrier to viral infection with important implications for prevention and therapy.
Publisher: Oxford University Press (OUP)
Date: 09-2013
DOI: 10.1095/BIOLREPROD.113.109561
Abstract: The mammary gland undergoes development and regression over the course of the ovarian cycle under the regulation of ovarian hormones. Macrophages are implicated as local mediators of this tissue remodeling and may also affect immune surveillance and tumor incidence. To investigate cycle-related changes in macrophage phenotype, mammary gland cells from naturally cycling Cfms-Gfp mice recovered at estrus, metestrus, diestrus, and proestrus were analyzed by flow cytometry. Macrophage expression of MHCII was highest in the proestrus phase, with a 1.6-fold increase compared to the metestrus phase. Similarly, macrophage expression of CD204 was 1.9-fold higher at proestrus compared to estrus. Conversely, macrophage expression of NKG2D was increased at metestrus and diestrus by 7-fold and 5-fold, respectively, compared to estrus. To investigate hormonal regulation of macrophage phenotype, an ovariectomy and hormone replacement model was utilized. Ovariectomized mice were stimulated with exogenous estradiol and progesterone to induce early alveolar development, then given progesterone receptor antagonist RU486 to elicit alveolar bud regression. Progesterone and estradiol in combination reduced macrophage expression of MHCII and CD204 by 5-fold and 3-fold, respectively, and increased macrophage expression of NKG2D by 4-fold. Administration of RU486, following estradiol and progesterone, reversed the macrophage phenotype. These results reveal an essential requirement for ovarian hormones in regulating macrophage phenotype in the mammary gland and indicate that progesterone is particularly critical for controlling macrophage antigen presentation and immune surveillance capacity.
Publisher: Elsevier BV
Date: 2021
Publisher: Oxford University Press (OUP)
Date: 25-04-2018
Abstract: Endometriosis is a benign gynaecological disorder, which affects 10% of reproductive-aged women and is characterized by endometrial cells from the lining of the uterus being found outside the uterine cavity. However, the pathophysiological mechanisms causing the development of this heterogeneous disease remain enigmatic, and a lack of effective biomarkers necessitates surgical intervention for diagnosis. There is international recognition that accurate non-invasive diagnostic tests and more effective therapies are urgently needed. Non-coding RNA (ncRNA) molecules, which are important regulators of cellular function, have been implicated in many chronic conditions. In endometriosis, transcriptome profiling of tissue s les and functional in vivo and in vitro studies demonstrate that ncRNAs are key contributors to the disease process. In this review, we outline the biogenesis of various ncRNAs relevant to endometriosis and then summarize the evidence indicating their roles in regulatory pathways that govern disease establishment and progression. Articles from 2000 to 2016 were selected for relevance, validity and quality, from results obtained in PubMed, MEDLINE and Google Scholar using the following search terms: ncRNA and reproduction ncRNA and endometriosis miRNA and endometriosis lncRNA and endometriosis siRNA and endometriosis endometriosis endometrial cervical ovary uterus reproductive tract. All articles were independently screened for eligibility by the authors. This review integrates extensive information from all relevant published studies focusing on microRNAs, long ncRNAs and short inhibitory RNAs in endometriosis. We outline the biological function and synthesis of microRNAs, long ncRNAs and short inhibitory RNAs and provide detailed findings from human research as well as functional studies carried out both in vitro and in vivo, including animal models. Although variability in findings between in idual studies exists, collectively, the extant literature justifies the conclusion that dysregulated ncRNAs are a significant element of the endometriosis condition. There is a compelling case that microRNAs, long non-coding RNAs and short inhibitory RNAs have the potential to influence endometriosis development and persistence through modulating inflammation, proliferation, angiogenesis and tissue remodelling. Rapid advances in ncRNA biomarker discovery and therapeutics relevant to endometriosis are emerging. Unravelling the significance of ncRNAs in endometriosis will pave the way for new diagnostic tests and identify new therapeutic targets and treatment approaches that have the potential to improve clinical options for women with this disabling condition.
Publisher: Oxford University Press (OUP)
Date: 12-1999
DOI: 10.1093/HUMREP/14.12.3069
Abstract: The cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) is synthesized in the female reproductive tract and has been implicated in the growth and development of the preimplantation embryo in rodent and livestock species. To examine the effect of GM-CSF on human embryo development in vitro, surplus frozen 2-4-cell embryos were cultured in media supplemented with 2 ng/ml recombinant human GM-CSF. The addition of cytokine increased the proportion of embryos that developed to the blastocyst stage from 30 to 76%. The developmental competence of these blastocysts, as assessed by hatching and attachment to extracellular matrix-coated culture dishes, was also improved by GM-CSF. The period in culture required for 50% of the total number of blastocysts to form was reduced by 14 h, and blastocysts grown in GM-CSF were found to contain approximately 35% more cells, due primarily to an increase in the size of the inner cell mass. The beneficial effect of GM-CSF was exerted in each of two sequential media systems (IVF-50/S2 and G1. 2/G2.2) and was independent of the formulation of recombinant cytokine that was used. These data indicate that GM-CSF may have a physiological role in promoting the development of the human embryo as it traverses the reproductive tract in vivo, and suggest that addition of this cytokine to embryo culture media may improve the yield of implantation-competent blastocysts in human in-vitro fertilization programmes.
Publisher: American Society for Clinical Investigation
Date: 02-10-2018
DOI: 10.1172/JCI122631
Publisher: Elsevier BV
Date: 10-2022
DOI: 10.1016/J.MAM.2022.101098
Abstract: Pregnancy complications including fetal growth restriction, preecl sia, and preterm birth, as well as gestational diabetes, affect one in every four to five pregnancies. Accumulating evidence indicates that increased production of reactive oxygen species accompanies these complications. Given that reactive oxygen species are cell stress-inducing agents, they may have a causal role in disease pathophysiology, although the exact mechanisms by which they contribute to pregnancy complications are not completely understood. Since many environmental and lifestyle factors and exposures are known to modulate reactive oxygen species production, the exposome of pregnant women could contribute to increased generation of reactive oxygen species. The objective of this review is to provide a comprehensive overview of the endogenous and exogenous exposome factors that regulate reactive species in healthy and complicated pregnancies. We also provide a description of dietary interventions aimed at the reduction of reactive species in order to attenuate adverse pregnancy outcome. Dietary interventions in general hold minimal risk in pregnancy and could therefore be considered a promising therapeutic approach.
Publisher: The American Association of Immunologists
Date: 08-2019
Abstract: Regulatory T cells (Tregs) are essential for maternal tolerance in allogeneic pregnancy. In preecl sia, Tregs are fewer and display aberrant phenotypes, particularly in the thymic Treg (tTreg) compartment, potentially because of insufficient priming to male partner alloantigens before conception. To investigate how tTregs as well as peripheral Tregs (pTregs) respond to male partner seminal fluid, Foxp3+CD4+ Tregs were examined in the uterus and uterus-draining lymph nodes in virgin estrus mice and 3.5 d postcoitum. Mating elicited 5-fold increases in uterine Tregs accompanied by extensive Treg proliferation in the uterus-draining lymph nodes, comprising 70% neuropilin 1+ tTregs and 30% neuropilin 1− pTregs. Proliferation marker Ki67 and suppressive competence markers Foxp3 and CTLA4 were induced after mating in both subsets, and Ki67, CTLA4, CD25, and GITR were higher in tTregs than in pTregs. Analysis by t-stochastic neighbor embedding confirmed phenotypically distinct tTreg and pTreg clusters, with the proportion of tTregs but not pTregs among CD4+ T cells expanding in response to seminal fluid. Bisulphite sequencing revealed increased demethylation of the Treg-specific demethylation region in the Foxp3 locus in tTregs but not pTregs after mating. These data show that tTregs and pTregs with distinct phenotypes both respond to seminal fluid priming, but the Foxp3 epigenetic signature is uniquely increased in tTregs. We conclude that reproductive tract tTregs as well as pTregs are sensitive to local regulation by seminal fluid, providing a candidate mechanism warranting evaluation for the potential to influence preecl sia susceptibility in women.
Location: United Kingdom of Great Britain and Northern Ireland
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Funder: Marsden Fund
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