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 J. Jenkins, Nicholas Topley, Simon A. Jones

Research output: Contribution to journalArticle

164 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)40-50
Number of pages11
JournalImmunity
Volume40
Issue number1
DOIs
Publication statusPublished - Jan 16 2014
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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