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

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dc.contributor.advisor Brint, Elizabeth K. en
dc.contributor.advisor Houston, Aileen M. en
dc.contributor.author Lyons, Caitríona M. en
dc.date.accessioned 2015-11-25T11:22:51Z
dc.date.issued 2015
dc.date.submitted 2015
dc.identifier.citation Lyons, 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.uri http://hdl.handle.net/10468/2094
dc.description.abstract Background/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.sponsorship Science Foundation Ireland (SFI Grant 10/RFP/BIC2737) en
dc.format.mimetype application/pdf en
dc.language.iso en en
dc.publisher University College Cork en
dc.rights © 2015, Caitríona M. Lyons. en
dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/3.0/ en
dc.subject TLR3 en
dc.subject TLR4 en
dc.subject Cross-talk en
dc.subject Fas (CD95) signalling en
dc.subject TLR signalling en
dc.subject Innate immunity en
dc.title Investigating the role of Fas (CD95) signalling in the modification of innate immune induced inflammation en
dc.type Doctoral thesis en
dc.type.qualificationlevel Doctoral en
dc.type.qualificationname PhD (Medicine and Health) en
dc.internal.availability Full text available en
dc.check.info Please note that Chapters 5-6 (pp.141-210) are unavailable due to a restriction requested by the author. en
dc.check.date 10000-01-01
dc.description.version Accepted Version
dc.contributor.funder Science Foundation Ireland en
dc.description.status Not peer reviewed en
dc.internal.school Medicine en
dc.internal.school Pathology en
dc.check.reason This thesis is due for publication or the author is actively seeking to publish this material en
dc.check.opt-out Not applicable en
dc.thesis.opt-out false
dc.check.chapterOfThesis - 5, 6
dc.check.embargoformat Both hard copy thesis and e-thesis en
ucc.workflow.supervisor e.brint@ucc.ie
dc.internal.conferring Summer Conferring 2015


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© 2015, Caitríona M. Lyons. Except where otherwise noted, this item's license is described as © 2015, Caitríona M. Lyons.
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