1. Interleukin-6 signaling drives fibrosis in unresolved inflammation.
- Author
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Fielding CA, Jones GW, McLoughlin RM, McLeod L, Hammond VJ, Uceda J, Williams AS, Lambie M, Foster TL, Liao CT, Rice CM, Greenhill CJ, Colmont CS, Hams E, Coles B, Kift-Morgan A, Newton Z, Craig KJ, Williams JD, Williams GT, Davies SJ, Humphreys IR, O'Donnell VB, Taylor PR, Jenkins BJ, Topley N, and Jones SA
- Subjects
- Acute Disease, Adoptive Transfer, Animals, Cells, Cultured, Chronic Disease, Disease Models, Animal, Extracellular Matrix immunology, Feedback, Physiological, Fibrosis, Humans, Interferon-gamma genetics, Interferon-gamma metabolism, Interleukin-6 genetics, Interleukin-6 immunology, Mice, Mice, Inbred C57BL, Mice, Knockout, STAT1 Transcription Factor genetics, STAT1 Transcription Factor metabolism, Signal Transduction, Th1 Cells transplantation, Interleukin-6 metabolism, Peritoneum pathology, Peritonitis genetics, Peritonitis pathology, Th1 Cells immunology
- 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., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
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