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Title: Regulation of acute inflamation by oncostatin M receptor-beta
Author: Hams, Emily
ISNI:       0000 0004 2747 4812
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2008
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Although the interleukin (IL)-6 related cytokine Oncostatin M (OSM) affects a variety of inflammatory events associated with disease progression, the function of OSM in the face of an inflammatory challenge remains unclear. In this thesis a peritoneal model of inflammation, in association with in vitro studies using human primary cell lines, has been used to define the influence of OSM on chemokine-mediated leukocyte recruitment. When compared to wild type mice (WT) the induction of peritoneal inflammation in Oncostatin M receptor-beta deficient mice (OSMR-KO) resulted in enhanced monocytic cell trafficking, with no differences in neutrophil or lymphocyte recruitment observed, suggesting that OSM control of leukocyte recruitment is functionally distinct from that of IL-6. Subsequent in vitro studies and an in vivo appraisal of inflammatory chemokine expression following peritoneal inflammation inferred that OSM regulation of CCL5 might account for the observed difference in monocytic cell trafficking. The OSM-mediated control of CCL5 is clearly distinct from the actions of IL-6, which acts as a more prominent in vivo regulator of CCL2 expression than OSM. Mechanistically, these studies inferred a hitherto unidentified interplay between OSM-mediated STAT signalling and NF-kappaB activation. In this respect, EMSA analysis of nuclear extracts from peritoneal membranes isolated during course of the inflammatory response showed that OSMR-KO mice display an enhanced profile of NF-kappaB activation as compared to WT mice. Initial in vivo appraisal of the role of OSMRg-mediated signalling in repeated episodes of inflammation and associated tissue damage suggest that OSM continues to regulate monocytic cell trafficking throughout recurrent inflammatory episodes and does not play a significant role in inflammation-associated peritoneal tissue damage, again a finding clearly distinct from the observed effects of IL-6 in tissue injury. These findings suggest that activation of gp 130 by IL-6 and OSM trigger distinct inflammatory responses to affect individual aspects of leukocyte trafficking.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available