TY - JOUR
T1 - Interleukin-6 signaling drives fibrosis in unresolved inflammation
AU - Fielding, Ceri A.
AU - Jones, Gareth W.
AU - McLoughlin, Rachel M.
AU - McLeod, Louise
AU - Hammond, Victoria J.
AU - Uceda, Javier
AU - Williams, Anwen S.
AU - Lambie, Mark
AU - Foster, Thomas L.
AU - Liao, Chia Te
AU - Rice, Christopher M.
AU - Greenhill, Claire J.
AU - Colmont, Chantal S.
AU - Hams, Emily
AU - Coles, Barbara
AU - Kift-Morgan, Ann
AU - Newton, Zarabeth
AU - Craig, Katherine J.
AU - Williams, John D.
AU - Williams, Geraint T.
AU - Davies, Simon J.
AU - Humphreys, Ian R.
AU - O'Donnell, Valerie B.
AU - Taylor, Philip R.
AU - Jenkins, Brendan J.
AU - Topley, Nicholas
AU - Jones, Simon A.
PY - 2014/1/16
Y1 - 2014/1/16
N2 - 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.
AB - 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.
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U2 - 10.1016/j.immuni.2013.10.022
DO - 10.1016/j.immuni.2013.10.022
M3 - Article
C2 - 24412616
AN - SCOPUS:84892476632
VL - 40
SP - 40
EP - 50
JO - Immunity
JF - Immunity
SN - 1074-7613
IS - 1
ER -