Interleukin-6 signaling drives fibrosis in unresolved inflammation.

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.

• Authors: 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 Williams, Simon J Davies, Ian R Humphreys, Valerie B O'Donnell, Philip R Taylor, Brendan J Jenkins, Nicholas Topley, Simon A Jones
• Journal: Immunity (Immunity) Vol. 40 Issue 1 Pg. 40-50 (Jan 16 2014) ISSN: 1097-4180 [Electronic] United States
• PMID: 24412616 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier Inc. All rights reserved.

Chemical References

• Interleukin-6
• STAT1 Transcription Factor
• Interferon-gamma

Topics

• Acute Disease
• Adoptive Transfer
• Animals
• Cells, Cultured
• Chronic Disease
• Disease Models, Animal
• Extracellular Matrix (immunology)
• Feedback, Physiological
• Fibrosis
• Humans
• Interferon-gamma (genetics, metabolism)
• Interleukin-6 (genetics, immunology, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Peritoneum (pathology)
• Peritonitis (genetics, pathology)
• STAT1 Transcription Factor (genetics, metabolism)
• Signal Transduction
• Th1 Cells (immunology, transplantation)