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.
N1 - Funding Information:
Research was supported by The Wellcome Trust (to S.A.J. and N.T., Ref. 065961, 069630, 079044), Arthritis Research UK (to S.A.J. and G.W.J.; Ref. 20305, 19796, 19381, 18286), Kidney Research UK (to C.A.F.; Ref. CDF2/2006), the Kenyon Gilson EPS Research Fund (to C.A.F., S.A.J., and N.T.), and an MRC capacity-building PhD Studentship (to S.A.J. and V.B.O’D.). B.J.J. is supported by Senior Fellowship Awards from the Sylvia and Charles Viertel Charitable Foundation, an Operational Infrastructure Support Program from the Victorian Government of Australia, and a National Health and Medical Research Council of Australia Project Grant. J.U. is recipient of a CITER Summer Student Stipend. The authors appreciate the support of I. Campbell, G. Wilkinson, and A. Gallimore and are also indebted to G. Stockinger for her support and encouragement. Finally, we thank the Peritoneal Biopsy Registry and Bro Taf NHS Trust surgical teams for clinical samples.
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
SN - 1074-7613
VL - 40
SP - 40
EP - 50
JO - Immunity
JF - Immunity
IS - 1
ER -
