Immunity
Volume 40, Issue 1, 16 January 2014, Pages 40-50
Journal home page for Immunity

Article
Interleukin-6 Signaling Drives Fibrosis in Unresolved Inflammation

https://doi.org/10.1016/j.immuni.2013.10.022Get rights and content
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Highlights

  • Repeated acute resolving inflammation leads to excessive tissue damage

  • IL-6 regulates profibrotic IFN-γ-secreting T cells

  • IFN-γ increases detrimental STAT1 signaling in stromal tissue

  • STAT1 activity alters homeostatic control of extracellular matrix to promote fibrosis

Summary

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.

Cited by (0)

6

These authors contributed equally to this work

7

These authors contributed equally to this work and are co-senior authors

8

Present address: School of Biochemistry & Immunology, Trinity College Dublin, Dublin, Ireland

9

Present address: Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland