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Interleukin-6 signaling drives fibrosis in unresolved inflammation

Fielding, Ceri A., Jones, Gareth W., McLoughlin, Rachel M., McLeod, Louise, Hammond, Victoria J., Uceda, Javier, Williams, Anwen S., Lambie, Mark, Foster, Thomas L., Liao, Chia-Te, Rice, Christopher M., Greenhill, Claire J., Colmont, Chantal S., Hams, Emily, Coles, Barbara, Kift-Morgan, Ann, Newton, Zarabeth, Craig, Katherine J., Williams, John D., Williams, Geraint T., Davies, Simon J., Humphreys, Ian R., O'Donnell, Valerie B., Taylor, Philip R., Jenkins, Brendan J., Topley, Nicholas and Jones, Simon A. 2014. Interleukin-6 signaling drives fibrosis in unresolved inflammation. Immunity 40 (1) , pp. 40-50. 10.1016/j.immuni.2013.10.022

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Abstract

Fibrosis in response to tissue damage or persistent inflammation is a pathological hallmark of many chronic degenerative diseases. By using a model of acute peritoneal inflammation, we have examined how repeated inflammatory activation promotes fibrotic tissue injury. In this context, fibrosis was strictly dependent on interleukin-6 (IL-6). Repeat inflammation induced IL-6-mediated T helper 1 (Th1) cell effector commitment and the emergence of STAT1 (signal transducer and activator of transcription-1) activity within the peritoneal membrane. Fibrosis was not observed in mice lacking interferon-γ (IFN-γ), STAT1, or RAG-1. Here, IFN-γ and STAT1 signaling disrupted the turnover of extracellular matrix by metalloproteases. Whereas IL-6-deficient mice resisted fibrosis, transfer of polarized Th1 cells or inhibition of MMP activity reversed this outcome. Thus, IL-6 causes compromised tissue repair by shifting acute inflammation into a more chronic profibrotic state through induction of Th1 cell responses as a consequence of recurrent inflammation.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > R Medicine (General)
Additional Information: This is an open access article under the terms of the CC-BY license.
Publisher: Elsevier (Cell Press)
ISSN: 1074-7613
Funders: MRC, Wellcome Trust
Date of First Compliant Deposit: 30 March 2016
Date of Acceptance: 28 October 2013
Last Modified: 20 Jan 2021 09:30
URI: http://orca.cf.ac.uk/id/eprint/61183

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