Investigating the role of Fas (CD95) signalling in the modification of innate immune induced inflammation

dc.check.chapterOfThesis- 5, 6
dc.check.date10000-01-01
dc.check.embargoformatBoth hard copy thesis and e-thesisen
dc.check.infoPlease note that Chapters 5-6 (pp.141-210) are unavailable due to a restriction requested by the author.en
dc.check.opt-outNot applicableen
dc.check.reasonThis thesis is due for publication or the author is actively seeking to publish this materialen
dc.contributor.advisorBrint, Elizabeth K.en
dc.contributor.advisorHouston, Aileen M.en
dc.contributor.authorLyons, Caitríona M.en
dc.contributor.funderScience Foundation Irelanden
dc.date.accessioned2015-11-25T11:22:51Z
dc.date.issued2015
dc.date.submitted2015
dc.description.abstractBackground/Aim: It has been demonstrated that a number of pathologies occur as a result of dysregulation of the immune system. Whilst classically associated with apoptosis, the Fas (CD95) signalling pathway plays a role in inflammation. Studies have demonstrated that Fas activation augments TLR4-mediated MyD88-dependent cytokine production. Studies have also shown that the Fas adapter protein FADD is required for RIG-I-induced IFNβ production. As a similar signalling pathway exists between RIG-I, TLR3 and the MyD88- independent of TLR4, we hypothesised that Fas activation may modulate both TLR3- and TLR4-induced cytokine production. Results: Fas activation reduced poly I:C-induced IFNβ, IL-8, IL-10 and TNFα production whilst augmenting poly I:C-, poly A:U- and Sendai virus-induced IP-10 production. TLR3-, RIG-I- and MDA5-induced IP-10 luciferase activation were inhibited by the Fas adapter protein FADD using overexpression studies. Poly I:C-induced phosphorylation of p-38 and JNK MAPK were reduced by Fas activation. Overexpression of FADD induced AP-1 luciferase activation. Point mutations in the AP-1 binding site enhanced poly I:C-induced IP- 10 production. LPS-induced IL-10, IL-12, IL-8 and TNFα production were enhanced by Fas activation, whilst reducing LPS-induced IFNβ production. Absence of FADD using FADD-/- MEFs resulted in impaired IFNβ production. Overexpression studies using FADD augmented TLR4-, MyD88- and TRIF-induced IFNβ luciferase activation. Overexpression studies also suggested that enhanced TLR4-induced IFNβ production was independent of NFκB activation. Conclusion: Viral-induced IP-10 production is augmented by Fas activation by reducing the phosphorylation of p-38 and JNK MAPKs, modulating AP-1 activation. The Fas adapterprotein FADD is required for TLR4-induced IFNβ production. Studies presented here demonstrate that the Fas signalling pathway can therefore modulate the immune response. Our data demonstrates that this modulatory effect is mediated by its adapter protein FADD, tailoring the immune response by acting as a molecular switch. This ensures the appropriate immune response is mounted, thus preventing an exacerbated immune response.en
dc.description.sponsorshipScience Foundation Ireland (SFI Grant 10/RFP/BIC2737)en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Version
dc.format.mimetypeapplication/pdfen
dc.identifier.citationLyons, C. M. 2015. Investigating the role of Fas (CD95) signalling in the modification of innate immune induced inflammation. PhD Thesis, University College Cork.en
dc.identifier.urihttps://hdl.handle.net/10468/2094
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2015, Caitríona M. Lyons.en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/en
dc.subjectTLR3en
dc.subjectTLR4en
dc.subjectCross-talken
dc.subjectFas (CD95) signallingen
dc.subjectTLR signallingen
dc.subjectInnate immunityen
dc.thesis.opt-outfalse
dc.titleInvestigating the role of Fas (CD95) signalling in the modification of innate immune induced inflammationen
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD (Medicine and Health)en
ucc.workflow.supervisore.brint@ucc.ie
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