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Title: IL-6 and PGE2 regulate intestinal crypt homeostasis by autocrine and paracrine pathways
Author: Jeffery, Victoria
ISNI:       0000 0004 7227 3593
Awarding Body: University of East Anglia
Current Institution: University of East Anglia
Date of Award: 2017
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The intestinal epithelium is the most rapidly renewing tissue in the body. Dynamic selfrenewal in the intestine is achieved through continuous proliferation of intestinal stem cells, and is under the tight regulation of numerous signalling pathways. IL-6 and PGE2 are pleiotropic cytokines, with well characterised roles in inflammation and intestinal tumorigenesis; however the roles for IL-6 and PGE2 in intestinal renewal during homeostasis remain unknown. The aim of this research was to determine the mechanisms through which autocrine and paracrine IL-6 and PGE2 regulate tissue renewal in the small intestine and colon, respectively, during homeostasis. This work also aimed to investigate a potential source of IL-6 and PGE2 in the intestinal lamina propria, the eosinophil. This thesis demonstrates that in the mouse small intestine, IL-6 signalling induces pSTAT3 activation in Paneth cells, which was shown to be the site of IL-6 receptor expression. This induced an increase in crypt cell proliferation and ISC expansion of small intestinal crypts, most likely through IL-6-classic signalling, with involvement of the WNT signalling pathway. The colonic epithelium expresses COX enzymes for PGE2 synthesis, and EP1-4 receptors for PGE2 signal transduction. Autocrine PGE2 signalling was required for colonic crypt cell proliferation during steady state renewal, which was mediated through the EP1/EP3 receptors. Paracrine signalling through the IL-6 and PGE2 pathways also induced small intestinal and colonic crypt proliferation respectively. A potential paracrine source of IL-6 and PGE, that resides in the intestinal lamina propria during health is the eosinophil. A novel spatial relationship between eosinophils and the stem cell niche (site of renewal) and crypt top (site of regeneration) was identified, suggesting that eosinophils play a role in modulating epithelial cell renewal during homeostasis. This work demonstrates that autocrine and paracrine IL-6 and PGE2 signalling is required for the maintenance of intestinal homeostasis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available