ORCID Profile
0000-0002-7904-7340
Current Organisation
University of Adelaide
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Publisher: Oxford University Press (OUP)
Date: 2006
DOI: 10.1095/BIOLREPROD.105.043729
Abstract: Peroxisome proliferator-activated receptor-gamma (PPARG) and PPAR-alpha (PPARA) control metabolic processes in many cell types and act as anti-inflammatory regulators in macrophages. PPAR-activating ligands include thiazolidinediones (TZDs), such as troglitazone, once frequently used to treat insulin resistance as well as symptoms of polycystic ovary syndrome (PCOS). Since macrophages within the ovary mediate optimal follicle development, TZD actions to improve PCOS symptoms are likely to be partly mediated through these specifically localized immune cells. In mouse ovary, PPARG protein was expressed in granulosa cells and in isolated cells localized to theca, stroma, and corpora lutea, consistent with EMR1+ macrophages. Isolation of immune cells (EMR1+ or H2+) showed that Pparg and Ppara were expressed in ovarian macrophages at much higher levels than in peritoneal macrophages. Ovulatory human chorionic gonadotropin downregulated expression of Pparg and Ppara in EMR1+ ovarian macrophages, but no hormonal responsiveness was observed in H2+ cells. Downstream anti-inflammatory effects of PPARG activation were analyzed by in vitro treatment of isolated macrophages with troglitazone. Interleukin-1 beta (Il1b) expression was not altered, and tumor necrosis factor-alpha (Tnf) expression was affected in peritoneal macrophages only. In ovarian macrophages, inducible nitric oxide synthase (Nos2), an important proinflammatory enzyme that regulates ovulation, was significantly reduced by troglitazone treatment, an effect that was restricted to cells from the preovulatory ovary. Thus, expression of PPARs within ovarian macrophages is hormonally regulated, reflecting the changing roles of these cells during the ovulatory cycle. Additionally, ovarian macrophages respond directly to troglitazone to downregulate expression of proinflammatory Nos2, providing mechanistic information about ovarian effects of TZD treatment.
Publisher: Baishideng Publishing Group Inc.
Date: 2012
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: Oxford University Press (OUP)
Date: 02-1996
DOI: 10.1095/BIOLREPROD54.2.436
Abstract: The ovulatory process resembles an inflammatory reaction with an infiltration of leukocytes, production of inflammatory mediators such as cytokines, and a general edema and hyperemia. Nitric oxide (NO), a potent vasodilator and the main mediator of macrophage tumoricidal and bacteriocidal activities, is known to participate in inflammatory reactions and has been shown to mediate the interleukin-1 beta (IL-1 beta)-directed tissue-remodeling events within the ovary. The regulation by NO of ovulation rate, leukocyte distribution, and steroid release in the rat ovary was investigated through use of a combination of in vivo and in vitro models of ovulation and a competitive inhibitor, N-omega-nitro-L-arginine methyl ester (L-NAME), of the NO synthase (NOS) enzyme. Subcutaneous L-NAME (1.5 x 10(-4) mol/kg) administration significantly reduced the in vivo ovulation rate of eCG/hCG-primed rats (L-NAME-treated: 10.6 +/- 1.8 [mean +/- SEM] oocytes per ovary [O/O], 11.0 +/- 1.2 rupture sites per ovary [RS/O] saline-treated: 18.0 +/- 1.8 O/O, 19.4 +/- 1.1 RS/O p < 0.01) at 20 h post-hCG. These results were reflected in vitro, where addition of L-NAME (3.5 x 10(-5) mol/L) to LH (0.1 microgram/ml)-perfused ovaries decreased ovulation rate from 8.2 +/- 1.6 to 2.7 +/- 1 ovulations per ovary (p < 0.05) and simultaneously decreased nitrite accumulation at the completion of perfusions from 16.5 +/- 1.9 to 4.1 +/- 0.5 nmol/ml (p < 0.001). The addition of L-NAME to LH+IL-1 beta (4 ng/ml)-perfused ovaries decreased ovulation rate from 15.2 +/- 2.4 to 0.8 +/- 0.8 ovulations per ovary (p < 0.001) and simultaneously decreased nitrite accumulation at 22 h from 22.8 +/- 2.2 to 1.9 +/- 0.6 nmol/ml (p < 0.001). Studies analyzing and manipulating perfusion flow rate indicated that the L-NAME effects on ovulation rate are primarily due to a reduction in flow rate resulting from inhibition of NO, which may be a consequence of the known vasoconstrictor effects of NOS inhibitors. The observed reduction of in vivo ovulation rate by NO inhibition at 20 h post-hCG was associated with a significant reduction in thecal MCA149+ neutrophils at 12 h post-hCG, the expected time of ovulation (L-NAME-treated: 98.4 +/- 9.2 cells per thecal area saline-treated: 211.5 +/- 11.5 cells per thecal area p < 0.001), while ED1+ monocytes/macrophages underwent similar but nonsignificant changes. Plasma (20 h post-hCG) and perfusate progesterone were not different with L-NAME treatment, while perfusate estradiol levels were markedly reduced upon addition of L-NAME, suggesting a role for NO in ovulation but not in the process of luteinization. In summary, deprivation of NO by use of the competitive inhibitor, L-NAME, led to fewer ovulations, reduced accumulation of nitrite, a decreased neutrophil count in the theca of preovulatory follicles, and reduced estradiol secretion, while progesterone release remained unaffected. The NO pathway may therefore play an important role in the regulation of ovulation and the mediation of IL-1 beta's pro-ovulatory effects. There are likely to be primarily vascular effects, but also a nonvascular component, to the NO regulation of ovulation, with both components indirectly affecting ovulatory leukocyte distribution and steroid secretion.
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: Mary Ann Liebert Inc
Date: 05-2015
Abstract: The pathogenesis of nonalcoholic steatohepatitis is primarily an immune-driven disease and a known factor associated with treatment failure of chronic hepatitis C with interferon (IFN) and ribavirin. We studied the hepatocyte response in a model of steatosis at the transcriptome level and the antiviral action of IFN against hepatitis C virus (HCV) in this setting. In this study, we have shown that lipid loading (oleic acid and palmitic acid, OA:PA) of Huh-7 cells leads to increased expression of classical interferon-stimulated genes (ISGs) and NF-κβ-dependent pro-inflammatory genes. A selective blocker of Toll-like receptor (TLR)2 signaling suppressed NF-κβ promoter activity by OA:PA, suggesting that free fatty acids (FFAs) act as a TLR2 pathogen-associated molecular pattern. Furthermore, in the presence of OA:PA, IFN stimulation and HCV infection (Jc1) increased ISG expression. Somewhat counterintuitive to the increase in ISGs, the anti-HCV activity of IFN was attenuated in the presence of OA:PA. Interestingly, the combination of OA:PA, HCV, and IFN-α stimulation resulted in a significant increase in CXCL8 protein production, a cytokine known to have anti-IFN modulating activity. Thus, in an in vitro model of steatosis, the FFAs OA and PA drive an NF-κβ-dependent inflammatory and ISG gene expression profile via TLR2 activation. Furthermore, FFA synergistically increases IFN-driven gene expression that may account for HCV treatment failure in vivo.
Publisher: The Endocrine Society
Date: 11-2003
DOI: 10.1210/EN.2003-0584
Publisher: Elsevier BV
Date: 06-2016
DOI: 10.1016/J.VIROL.2016.02.016
Abstract: The spatiotemporal dynamics of Hepatitis C Virus (HCV) RNA localisation are poorly understood. To address this we engineered HCV genomes harbouring MS2 bacteriophage RNA stem-loops within the 3'-untranslated region to allow tracking of HCV RNA via specific interaction with a MS2-Coat-mCherry fusion protein. Despite the impact of these insertions on viral fitness, live imaging revealed that replication of tagged-HCV genomes induced specific redistribution of the mCherry-tagged-MS2-Coat protein to motile and static foci. Further analysis showed that HCV RNA was associated with NS5A in both static and motile structures while a subset of motile NS5A structures was devoid of HCV RNA. Further investigation of viral RNA traffic with respect to lipid droplets (LDs) revealed HCV RNA-positive structures in close association with LDs. These studies provide new insights into the dynamics of HCV RNA traffic with NS5A and LDs and provide a platform for future investigations of HCV replication and assembly.
Publisher: Cold Spring Harbor Laboratory
Date: 11-12-2018
DOI: 10.1101/493098
Abstract: Viperin is an interferon-inducible protein that is pivotal for eliciting an effective immune response against an array of erse viral pathogens. Here we describe a mechanism of viperin’s broad antiviral activity by demonstrating the protein’s ability to synergistically enhance the innate immune dsDNA signalling pathway to limit viral infection. Viperin co-localised with the key signalling molecules of the innate immune dsDNA sensing pathway, STING and TBK1 binding directly to STING and inducing enhanced K63-linked polyubiquitination of TBK1. Subsequent analysis identified viperin’s necessity to bind the cytosolic iron-sulphur assembly component 2A, to prolong its enhancement of the type-I interferon response to aberrant dsDNA. Here we show that viperin facilitates the formation of a signalling enhanceosome, to coordinate efficient signal transduction following activation of the dsDNA signalling pathway which results in an enhanced antiviral state. We also provide evidence for viperin’s radical SAM enzymatic activity to self-limit its immunomodulatory functions. This data further defines viperin’s role as a positive regulator of innate immune signalling, offering a mechanism of viperin’s broad antiviral capacity.
Publisher: Springer Science and Business Media LLC
Date: 30-06-2017
DOI: 10.1038/S41598-017-04138-1
Abstract: Zika virus (ZIKV) infection has emerged as a global health threat and infection of pregnant women causes intrauterine growth restriction, spontaneous abortion and microcephaly in newborns. Here we show using biologically relevant cells of neural and placental origin that following ZIKV infection, there is attenuation of the cellular innate response characterised by reduced expression of IFN-β and associated interferon stimulated genes (ISGs). One such ISG is viperin that has well documented antiviral activity against a wide range of viruses. Expression of viperin in cultured cells resulted in significant impairment of ZIKV replication, while MEFs derived from CRISPR/Cas9 derived viperin −/− mice replicated ZIKV to higher titers compared to their WT counterparts. These results suggest that ZIKV can attenuate ISG expression to avoid the cellular antiviral innate response, thus allowing the virus to replicate unchecked. Moreover, we have identified that the ISG viperin has significant anti-ZIKV activity. Further understanding of how ZIKV perturbs the ISG response and the molecular mechanisms utilised by viperin to suppress ZIKV replication will aid in our understanding of ZIKV biology, pathogenesis and possible design of novel antiviral strategies.
Publisher: Oxford University Press (OUP)
Date: 05-2002
DOI: 10.1095/BIOLREPROD66.5.1548
Abstract: Leptin is a product of the ob gene that is produced primarily by adipose tissue. Leptin and its receptors are found within the ovary, but it is unclear what function this hormone has in the ovary. Using immunohistochemistry, we determined that leptin is found in most cell types in the murine ovary, with the highest staining levels observed in the oocyte. Leptin receptor was also expressed in all of the main ovarian cell types, with the thecal cell layer exhibiting the highest staining levels. Leptin administration did not affect spontaneous or induced maturation of either isolated denuded oocytes or cumulus-oocyte complexes, but it did significantly increase the rate of meiotic resumption in preovulatory follicle-enclosed oocytes (P < 0.01). Measurements of cAMP within oocytes cultured with leptin showed that this enhanced ability to resume meiosis does not occur via activation of phosphodiesterase 3B and subsequent cAMP reduction. These results provide evidence that leptin affects oocyte maturation when the oocyte is cultured within its normal follicular environment. It is suggested that leptin may induce the production of another factor, possibly from thecal cells, that directly or indirectly acts on the oocyte to initiate germinal vesicle breakdown in this species.
Publisher: Bioscientifica
Date: 06-2002
Abstract: Leptin is expressed by adipocytes and is thought to play a role in regulating food intake and in reproduction. It has been demonstrated that acute leptin administration to immature gonadotrophin-primed rats in vivo inhibits ovulation and causes a decline in food intake. However, feed restriction alone does not inhibit ovulation. Two experiments were designed to investigate the mechanism of leptin-induced inhibition of ovulation. In the first experiment, which was prompted by the importance of ovarian leucocytes in ovulation, the role of leucocytes in leptin-induced inhibition of ovulation was investigated. The second experiment investigated whether high leptin concentrations could inhibit other factors important to ovulation, such as meiotic competence of oocytes, granulosa cell proliferation, steroid or PGE(2) release, and interleukin 1beta production, in vitro. In the first experiment, the populations of neutrophils and monocytes-macrophages in the preovulatory follicles of gonadotrophin-primed, leptin-treated and -untreated rats were examined. A decrease in food intake, as a result of either leptin treatment or feed restriction, specifically reduced the numbers of neutrophils and monocytes-macrophages infiltrating the theca interna of preovulatory follicles without affecting the numbers found in the stroma. The findings show that reduced infiltration of thecal neutrophils and macrophages into preovulatory follicles is a response to reduced food intake. Furthermore, this reduction is not the direct cause of the leptin-induced inhibition of ovulation. In the second experiment, ovarian follicles were cultured for 4 or 12 h in the presence or absence of the following hormones: FSH (500 miu), insulin-like growth factor I (IGF-I) (50 ng ml(-1)), LH (100 ng ml(-1)) and leptin (300 ng ml(-1)). The results demonstrated that high concentrations of leptin in follicle culture do not affect meiotic maturation or steroid release, but tend to inhibit release of PGE 2 (although this result was not significant). DNA synthesis in granulosa cells was not inhibited by leptin in FSH- and IGF-I-supplemented culture media. These results are in agreement with previous studies that have shown that leptin inhibits the stimulatory effects of IGF-I on FSH-stimulated oestradiol production in rat granulosa cells without affecting progesterone production. In summary, leptin does not appear to have an adverse effect on the components of ovulation tested in this study, and therefore must impact on the ovulatory cascade in a way that remains to be defined.
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: Oxford University Press (OUP)
Date: 05-1998
DOI: 10.1095/BIOLREPROD58.5.1266
Abstract: Evidence that cytokines have important roles in ovulation is accumulating, with various cytokines having been found to influence the ovulatory cascade. Interleukin (IL)-6 is a pluripotent cytokine involved in inflammatory reactions, and it has been demonstrated in high concentrations in human ovarian follicular fluid and in vitro in secretions from the ovary. We set out to determine the effect this cytokine has on ovulation rate and steroidogenesis in the in vitro-perfused rat ovary. Preovulatory ovaries were taken from eCG-primed animals, and ovulation was induced by LH (100 ng/ml) alone or in combination with cytokine. Ovaries in the IL-6/LH groups (IL-6 concentration of 0.19 nM or 1.9 nM) did not have ovulation rates different from ovaries in the LH-only group. Ovaries in the LH/IL-1beta group ovulated more oocytes than ovaries in the LH-only group (LH/IL-1beta =11+/-1.8 oocytes LH alone=4.9+/-1.1 p=0.015) and the IL-6/LH/IL-1beta group (LH/IL-1beta/IL-6 [0.19 nM]=4+/-1.40 LH/IL-1beta=11+/-1.8 p=0.009). We have found that 1) exogenous IL-6 did not significantly alter the LH-induced ovulation rate but significantly reduced the LH/IL-1beta-induced ovulation rate 2) exogenous IL-6 did not alter LH-induced progesterone levels measured at time points during the perfusion period, but the average increase in progesterone over basal level was stimulated by IL-6 3) exogenous IL-6 did not affect LH-induced estradiol production 4) exogenous IL-6 did not affect LH-induced androstenedione production but increased LH/IL-1beta-induced production 5) exogenous IL-6 did not affect LH-induced prostaglandin E2 production. This study demonstrates that IL-6 does not play a role in regulating ovulation induced by LH in vitro but is capable of reducing LH/IL-1beta-enhanced ovulation rates. In addition, IL-6 may play a role in the regulation of ovarian steroid production.
Publisher: The Endocrine Society
Date: 06-2000
Abstract: Leptin, a hormonal product of the Lep gene, is expressed by adipocytes and is thought to play a role in regulating food intake and reproduction. The leptin protein has been localized in many reproductive tissues, including the ovary. Several publications indicate that the ovary is directly affected by leptin and that leptin may be a factor linking obesity and reproductive dysfunction. In this study, the effect of systemic leptin administration on ovulation in the rat ovary, both in vivo and in vitro, was investigated. Ip administration of leptin (30 μg at 3 hourly intervals for 15 h) to immature gonadotropin-primed rats caused a decline in ovulation in vivo, from 15.9 ± 2.0 oocytes in the control animals to 5.3 ± 1.6 oocytes in the leptin-treated animals (P & 0.001). Plasma progesterone and estradiol levels were analyzed immediately before ovulation, and neither was altered significantly in animals receiving the leptin treatment. Food consumption and body weight decreased following leptin treatment however, a loss in body weight alone (pair-fed controls) was insufficient to explain the decrease in ovulation observed in the leptin-treated animals. In vitro perfusion of FSH-primed whole ovaries showed that treatment with leptin in combination with LH significantly decreased ovulations from 5.7 ± 1.6 per ovary perfused with LH alone to 1.3 ± 0.6 in those with LH and 1 μg/ml leptin (P & 0.05). Progesterone and estradiol levels in the s les taken during the perfusion period were unaffected by leptin treatment. In summary, leptin administration resulted in fewer ovulations, both in vivo and in vitro, but did not influence steroid levels. Systemic leptin administration at these doses can therefore inhibit ovulation, a process that occurs through a direct effect on the ovary.
Publisher: Microbiology Society
Date: 19-10-2021
DOI: 10.1099/JGV.0.001669
Abstract: Viperin has antiviral function against many viruses, including dengue virus (DENV), when studied in cells in culture. Here, the antiviral actions of viperin were defined both in vitro and in a mouse in vivo model of DENV infection. Murine embryonic fibroblasts (MEFs) derived from mice lacking viperin (vip −/− ) showed enhanced DENV infection, accompanied by increased IFN-β and induction of ISGs IFIT1 and CXCL-10 but not IRF7, when compared to wild-type (WT) MEFs. In contrast, subcutaneous challenge of immunocompetent WT and vip −/− mice with DENV did not result in enhanced infection. Intracranial infection with DENV resulted in body weight loss and neurological disease with a moderate increase in mortality in vip −/− compared with WT mice, although this was not accompanied by altered brain morphology, immune cell infiltration or DENV RNA level in the brain. Similarly, DENV induction of IFN-β, IFIT1, CXCL-10, IRF7 and TNF-α was not significantly different in WT and vip −/− mouse brain, although there was a modest but significant increase in DENV induction of IL-6 and IfI27la in the absence of viperin. NanoString nCounter analysis confirmed no significant difference in induction of a panel of inflammatory genes in WT compared to vip −/− DENV-infected mouse brains. Further, polyI:C stimulation of bone marrow-derived macrophages (BMDMs) induced TNF-α, IFN-β, IL-6 and Nos-2, but responses were not different in BMDMs generated from WT or vip −/− mice. Thus, while there is significant evidence of anti-DENV actions of viperin in some cell types in vitro , for DENV infection in vivo a lack of viperin does not affect systemic or brain susceptibility to DENV or induction of innate and inflammatory responses.
Publisher: Oxford University Press (OUP)
Date: 03-2004
Publisher: The Endocrine Society
Date: 02-2009
DOI: 10.1210/ME.2008-0387
Publisher: Life Science Alliance, LLC
Date: 09-06-2021
Abstract: Peroxisomes are recognized as significant platforms for the activation of antiviral innate immunity where stimulation of the key adapter molecule mitochondrial antiviral signaling protein (MAVS) within the RIG-I like receptor (RLR) pathway culminates in the up-regulation of hundreds of ISGs, some of which drive augmentation of multiple innate sensing pathways. However, whether ISGs can augment peroxisome-driven RLR signaling is currently unknown. Using a proteomics-based screening approach, we identified Pex19 as a binding partner of the ISG viperin. Viperin colocalized with numerous peroxisomal proteins and its interaction with Pex19 was in close association with lipid droplets, another emerging innate signaling platform. Augmentation of the RLR pathway by viperin was lost when Pex19 expression was reduced. Expression of organelle-specific MAVS demonstrated that viperin requires both mitochondria and peroxisome MAVS for optimal induction of IFN-β. These results suggest that viperin is required to enhance the antiviral cellular response with a possible role to position the peroxisome at the mitochondrial/MAM MAVS signaling synapse, furthering our understanding of the importance of multiple organelles driving the innate immune response against viral infection.
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.
No related grants have been discovered for Kylie Van der Hoek.