dc.contributor.advisor |
McCarthy, Justin V. |
en |
dc.contributor.author |
Agrawal, Vishal |
|
dc.date.accessioned |
2014-04-14T13:48:47Z |
|
dc.date.issued |
2014 |
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dc.date.submitted |
2014 |
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dc.identifier.citation |
Agrawal, 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.endpage |
222 |
|
dc.identifier.uri |
http://hdl.handle.net/10468/1517 |
|
dc.description.abstract |
The 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.sponsorship |
Science Foundation Ireland (09/IN.1/B2624) |
en |
dc.format.mimetype |
application/pdf |
en |
dc.language.iso |
en |
en |
dc.publisher |
University College Cork |
en |
dc.rights |
© 2014, Vishal Agrawal. |
en |
dc.rights.uri |
http://creativecommons.org/licenses/by-nc-nd/3.0/ |
en |
dc.subject |
Presenilin 1 |
en |
dc.subject |
Presenilin 2 |
en |
dc.subject |
Lipopolysaccharides (LPS) |
en |
dc.subject |
Interleukin-1 beta |
en |
dc.subject |
Tumor Necrosis Factor Alpha (TNFα) |
en |
dc.title |
The role of presenilin 1 and presenilin 2 in IL-1β-, LPS- and TNFα- mediated signalling events |
en |
dc.type |
Doctoral thesis |
en |
dc.type.qualificationlevel |
Doctoral |
en |
dc.type.qualificationname |
PhD (Science) |
en |
dc.internal.availability |
Full text not available |
en |
dc.check.info |
Indefinite |
en |
dc.check.date |
10000-01-01 |
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dc.description.version |
Accepted Version |
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dc.contributor.funder |
Science Foundation Ireland |
en |
dc.description.status |
Not peer reviewed |
en |
dc.internal.school |
Biochemistry |
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 |
No |
en |
dc.thesis.opt-out |
false |
|
dc.check.entireThesis |
Entire Thesis Restricted |
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dc.check.embargoformat |
Both hard copy thesis and e-thesis |
en |
ucc.workflow.supervisor |
jv.mccarthy@ucc.ie |
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dc.internal.conferring |
Summer Conferring 2014 |
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