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Title: Understanding the mechanisms of Interleukin-1α processing and secretion
Author: Tapia Olivares, Victor
ISNI:       0000 0004 9354 2369
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2020
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Inflammation is a biological response that protects the host against infection, promotes tissue repair and recovers tissue homeostasis. Understanding the mechanisms that regulate inflammation is essential, as inflammation can become a maladaptive response that leads to the development and exacerbation of many diseases. The cytokines of the Interleukin-1 (IL-1) family, namely IL-1α and IL-1β, initiate and propagate inflammatory responses. While IL-1α and IL-1β signal through the same IL-1 Receptor, they differ in their expression, protein interactions, subcellular distribution and secretory mechanisms. Research has widely focused in IL-1β secretion, while the mechanisms that regulate IL-1α function are poorly understood. The aim of this thesis was to investigate multiple aspects that distinctly regulate IL-1α secretion. Firstly, the work presented here shows that while IL-1α and other IL-1 family cytokines are secreted in absence of cell lysis, IL-1α has a distinct secretory pathway related to the proteases calpain-1/2 and it may be dissociated from membrane permeability in contrast to IL-1β. Secondly, IL-1α nuclear localization was found to inhibit IL-1α release and activation, and IL-1α pro-domain was found to be necessary for IL-1α stability and activation. Finally, a new method to screen the IL-1α interactome by enzymatic proximity labelling was set up, which will be used to find novel functions of IL-1α protein interactors. Thus, the findings in this thesis give new insights in the mechanisms that regulate IL-1α secretion, and contribute to the understanding of an inflammatory signalling pathway of therapeutic interest.
Supervisor: Allan, Stuart ; Lawrence, Catherine ; Brough, David Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: IL-1a ; Inflammation ; Interleukin-1