Interleukin-6 signaling drives fibrosis in unresolved inflammation

Ceri A Fielding, Gareth W Jones, Rachel M McLoughlin, Louise McLeod, Victoria J Hammond, Javier Uceda, Anwen S Williams, Mark Lambie, Thomas L Foster, Chia-Te Liao, Christopher M Rice, Claire J Greenhill, Chantal S Colmont, Emily Hams, Barbara Coles, Ann Kift-Morgan, Zarabeth Newton, Katherine J Craig, John D Williams, Geraint T WilliamsSimon J Davies, Ian R Humphreys, Valerie B O'Donnell, Philip R Taylor, Brendan John Jenkins, Nicholas Topley, Simon A Jones

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259 Citations (Scopus)


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
Publication statusPublished - 2014

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