The role of presenilin 1 and presenilin 2 in IL-1β-, LPS- and TNFα- mediated signalling events

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dc.check.date10000-01-01
dc.check.embargoformatBoth hard copy thesis and e-thesisen
dc.check.entireThesisEntire Thesis Restricted
dc.check.infoIndefiniteen
dc.check.opt-outNoen
dc.check.reasonThis thesis is due for publication or the author is actively seeking to publish this materialen
dc.contributor.advisorMcCarthy, Justin V.en
dc.contributor.authorAgrawal, Vishal
dc.contributor.funderScience Foundation Irelanden
dc.date.accessioned2014-04-14T13:48:47Z
dc.date.issued2014
dc.date.submitted2014
dc.description.abstractThe importance of γ-secretase protease activities in development, neurogenesis and the immune system are highlighted by the diversity of its substrates and phenotypic characterization of Presenilin (PS)-deficient transgenic animals. Since the discovery of Amyloid precursor protein (APP) and it’s cleavage by γ-secretase complexes, over 90 other type I membrane proteins have been identified as γ-secretase substrates. We have identified interleukin-1 (IL-1) receptor type I (IL-1R1), toll-like receptor 4 (TLR4) and tumour necrosis factor-α (TNFα) receptor-1 (TNFR1) as novel substrates for - secretase cleavage, which play an important role in innate immunity. In this study, using PS-deficient cells and PS-knockout animal models we examined the role of PS proteins, PS1 and PS2, in IL-1R1-, TLR4- and TNFR1- mediated inflammatory responses. Data presented show that in response to IL- 1β, lipopolysaccharide (LPS) or TNFα, immortalised fibroblasts from PS2- deficient animals have diminished production of specific cytokines and chemokine, with differential reduction in nuclear factor-κB (NF-κB) and (mitogen activated protein kinase) MAPK activities. In contrast, no defect in the response to IL-1β, LPS or TNFα was observed in PS1-deficient immortalised fibroblasts. These observations were confirmed using bone marrow-derived macrophages from PS2-null mice, which also display impaired responsiveness to IL-1β- and LPS, with decreased production of inflammatory cytokines. Furthermore, in whole animal in vivo responses, we show that PS2-deficient animals display ligand (IL-1β, LPS and TNFα)-dependent alterations in the production of specific pro-inflammatory cytokines or chemokines. Importantly, this reduced responsiveness to IL-1β, LPS or TNFα is independent of γ- secretase protease activity and γ-secretase cleavage of TNFR1, IL-1R1 or TLR4. These observations suggest a novel γ-secretase-independent role of PS2 in the regulation of innate immune responsiveness and challenge current concepts regarding the regulation of IL-1β-, LPS- and TNFα-mediated immune signalling.en
dc.description.sponsorshipScience Foundation Ireland (09/IN.1/B2624)en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Version
dc.format.mimetypeapplication/pdfen
dc.identifier.citationAgrawal, V. 2014. The role of presenilin 1 and presenilin 2 in IL-1β-, LPS- and TNFα- mediated signalling events. PhD Thesis, University College Cork.en
dc.identifier.endpage222
dc.identifier.urihttps://hdl.handle.net/10468/1517
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2014, Vishal Agrawal.en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/en
dc.subjectPresenilin 1en
dc.subjectPresenilin 2en
dc.subjectLipopolysaccharides (LPS)en
dc.subjectInterleukin-1 betaen
dc.subjectTumor Necrosis Factor Alpha (TNFα)en
dc.thesis.opt-outfalse
dc.titleThe role of presenilin 1 and presenilin 2 in IL-1β-, LPS- and TNFα- mediated signalling eventsen
dc.typeDoctoral thesisen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD (Science)en
ucc.workflow.supervisorjv.mccarthy@ucc.ie
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