ORCID Profile
0000-0001-7145-1843
Current Organisation
Trinity College Dublin
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Publisher: Elsevier BV
Date: 09-2006
DOI: 10.1016/J.BBRC.2006.06.148
Abstract: Macrophage migration inhibitory factor (MIF) is a well-described pro-inflammatory mediator that has also been implicated in the process of oncogenic transformation and tumor progression. However, despite the compelling evidence that MIF is overexpressed in, and contributes to, the pathology of inflammatory and malignant diseases the mechanisms that contribute to exaggerated expression of MIF have been poorly described. Here we show that hypoxia, and specifically HIF-1alpha, is a potent and rapid inducer of MIF expression. In addition, we demonstrate that hypoxia-induced MIF expression is dependent upon a HRE in the 5'UTR of the MIF gene but is further modulated by CREB expression. We propose a model where hypoxia-induced MIF expression is driven by HIF-1 but lified by hypoxia-induced degradation of CREB. Given the importance of MIF in inflammatory and malignant diseases these data reveal a HIF-1-mediated pathway as a potential therapeutic target for suppression of MIF expression in hypoxic tissues.
Publisher: Mary Ann Liebert Inc
Date: 08-0009
Abstract: RNA interference (RNAi) is one of the most promising tools for deciphering the human genome and has great therapeutic potential. However, its high target specificity limits its efficiency for therapeutic protection from viruses with high rates of genetic mutation. This limitation may be overcome by the expression of long hairpin RNAs (lhRNAs). Indeed, lhRNAs have been shown recently to have increased efficacy over short interfering RNAs (siRNAs) as protective antiviral agents. Here, we investigate the expression of lhRNAs and demonstrate unintended effects. We show that overexpressed lhRNAs are exported to the cytoplasm. As a consequence, we detect activation of innate immune signaling pathways by lhRNAs. With growing concerns about the complexity of cytoplasmic detection of dsRNAs by the innate immune machinery, this work highlights the need for closer scrutiny when using lhRNAs as potential antiviral agents.
Publisher: Frontiers Media SA
Date: 2012
Publisher: BMJ
Date: 07-04-2020
DOI: 10.1136/THORAXJNL-2019-214027
Abstract: Mutations in the cystic fibrosis transmembrane regulator ( CFTR ) gene form the basis of cystic fibrosis (CF). There remains an important knowledge gap in CF as to how diminished CFTR activity leads to the dominant inflammatory response within CF airways. To investigate if extracellular vesicles (EVs) contribute to inflammatory signalling in CF. EVs released from CFBE41o-, CuFi-5, 16HBE14o- and NuLi-1 cells were characterised by nanoparticle tracking analysis (NTA). EVs isolated from bronchoalveolar lavage fluid (BALF) from 30 people with CF (PWCF) were analysed by NTA and mass spectrometry and compared with controls. Neutrophils were isolated from the blood of 8 PWCF to examine neutrophil migration in the presence of CFBE41o- EVs. A significantly higher level of EVs were released from CFBE41o- (p .0001) and CuFi-5 (p=0.0209) relative to control cell lines. A significantly higher level of EVs were detected in BALF of PWCF, in three different age groups relative to controls (p=0.01, 0.001, 0.002). A significantly lower level of EVs were released from CFBE41o- (p .001) and CuFi-5 (p=0.0002) cell lines treated with CFTR modulators. Significant changes in the protein expression of 126 unique proteins was determined in EVs obtained from the BALF of PWCF of different age groups (p .001–0.05). A significant increase in chemotaxis of neutrophils derived from PWCF was observed in the presence of CFBE41o EVs (p=0.0024) compared with controls. This study demonstrates that EVs are produced in CF airway cells, have differential protein expression at different ages and drive neutrophil recruitment in CF.
Publisher: Springer Science and Business Media LLC
Date: 2014
Publisher: Frontiers Media SA
Date: 08-05-2014
Publisher: Springer Science and Business Media LLC
Date: 04-1994
DOI: 10.1007/BF02967228
No related grants have been discovered for Seamas Donnelly.