Interleukin-6 signaling drives fibrosis in unresolved inflammation

Ceri A. Fielding, Gareth Wyn Jones, Rachel Mary McLoughlin, Louise McLeod, Victoria J. Hammond, Javier Uceda, Anwen Sian Williams, Mark Lambie, Thomas L. Foster, Chia-Te Liao, Christopher M. Rice, Claire J. Greenhill, Chantal Sophie Colmont, Emily Hams, Barbara Coles, Ann Kift-Morgan, Zarabeth Newton, Katherine J. Craig, John David Williams, Geraint Trefor WilliamsSimon J. Davies, Ian R. Humphreys, Valerie Bridget O'Donnell, Philip Russel Taylor, Brendan J. Jenkins, Nicholas Topley, Simon Arnett Jones

Research output: Contribution to journalArticle (Academic Journal)peer-review

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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-gamma (IFN-gamma), STAT1, or RAG-1. Here, IFN-gamma 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.
Original languageEnglish
Pages (from-to)40-50
Number of pages11
Issue number1
Early online date9 Jan 2014
Publication statusPublished - 16 Jan 2014

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