Molecular mechanisms underpinning IFN-gamma and TNF-alpha synergy in intestinal epithelial cells

dc.check.date10000-01-01
dc.check.embargoformatHard bound copy in Library onlyen
dc.check.infoIndefiniteen
dc.check.opt-outYesen
dc.check.reasonThis thesis is due for publication or the author is actively seeking to publish this materialen
dc.check.typeNo Embargo Required
dc.contributor.advisorNally, Kennethen
dc.contributor.advisorMelgar, Silviaen
dc.contributor.advisorShanahan, Fergusen
dc.contributor.authorWoznicki, Jerzy A.
dc.contributor.funderScience Foundation Irelanden
dc.date.accessioned2015-11-03T09:52:50Z
dc.date.issued2014
dc.date.submitted2014
dc.description.abstractCytokine-driven signalling shapes immune homeostasis and guides inflammatory responses mainly through induction of specific gene expression programmes both within and outside the immune cell compartment. These transcriptional outputs are often amplified via cytokine synergy, which sets a stimulatory threshold that safeguards from exacerbated inflammation and immunopathology. In this study, we investigated the molecular mechanisms underpinning synergy between two pivotal Th1 cytokines, IFN-γ and TNF-α, in human intestinal epithelial cells. These two proinflammatory mediators induce a unique state of signalling and transcriptional synergy implicated in processes such as antiviral and antitumour immunity, intestinal barrier and pancreatic β-cell dysfunction. Since its discovery more than 30 years ago, this biological phenomenon remains, however, only partially defined. Here, using a functional genomics approach including RNAi perturbation screens and small-molecule inhibitors, we identified two new regulators of IFN-γ/TNF-α-induced chemokine and antiviral gene and protein expression, a Bcl-2 protein BCL-G and a histone demethylase UTX. We also discovered that IFN-γ/TNF-α synergise to trigger a coordinated shutdown of major receptor tyrosine kinases expression in colon cancer cells. Together, these findings extend our current understanding of how IFN-γ/TNF-α synergy elicits qualitatively and quantitatively distinct outputs in the intestinal epithelium. Given the well-documented role of this synergistic state in immunopathology of various disorders, our results may help to inform the identification of high quality and biologically relevant druggable targets for diseases characterised by an IFN-γ/TNF-α high immune signatureen
dc.description.statusNot peer revieweden
dc.description.versionAccepted Version
dc.format.mimetypeapplication/pdfen
dc.identifier.citationWoznicki, J.A. 2014. Molecular mechanisms underpinning IFN-gamma and TNF-alpha synergy in intestinal epithelial cells. PhD Thesis, University College Cork.en
dc.identifier.urihttps://hdl.handle.net/10468/2017
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2014, Jerzy A. Woznicki.en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/en
dc.subjectCytokinesen
dc.subjectIntestinal epithelial cellsen
dc.subjectSignal transductionen
dc.subjectEpigeneticsen
dc.subjectTranscriptional regulationen
dc.thesis.opt-outtrue
dc.titleMolecular mechanisms underpinning IFN-gamma and TNF-alpha synergy in intestinal epithelial cellsen
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD (Medicine and Health)en
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