Interleukin-6 signaling drives fibrosis in unresolved inflammation

Fielding, Ceri A. ORCID: https://orcid.org/0000-0002-5817-3153, Jones, Gareth W. ORCID: https://orcid.org/0000-0001-7297-9711, McLoughlin, Rachel M., McLeod, Louise, Hammond, Victoria J., Uceda, Javier, Williams, Anwen S. ORCID: https://orcid.org/0000-0003-3768-9940, Lambie, Mark, Foster, Thomas L., Liao, Chia-Te, Rice, Christopher M., Greenhill, Claire J., Colmont, Chantal S., Hams, Emily ORCID: https://orcid.org/0000-0002-9745-3246, Coles, Barbara, Kift-Morgan, Ann, Newton, Zarabeth, Craig, Katherine J., Williams, John D. ORCID: https://orcid.org/0000-0003-3768-9940, Williams, Geraint T. ORCID: https://orcid.org/0000-0003-3768-9940, Davies, Simon J., Humphreys, Ian R. ORCID: https://orcid.org/0000-0002-9512-5337, O'Donnell, Valerie B. ORCID: https://orcid.org/0000-0003-4089-8460, Taylor, Philip R. ORCID: https://orcid.org/0000-0003-0163-1421, Jenkins, Brendan J., Topley, Nicholas and Jones, Simon A. ORCID: https://orcid.org/0000-0001-7297-9711 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 Jun 2024 13:08
URI:	https://orca.cardiff.ac.uk/id/eprint/61183

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