Abstract
SummaryFibrosis 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.
Highlights
Fibrosis of connective tissues or organ structures is characterized by alterations in extracellular matrix deposition as a consequence of tissue damage or persistent inflammation (Wynn, 2007)
IFN-g and STAT1 signaling disrupted the turnover of extracellular matrix by metalloproteases
Inflammatory cytokines including interleukin-4 (IL-4), IL-13, transforming growth factor-b (TGF-b), and oncostatin-M have all been linked to the development of fibrosis in autoimmune conditions such as systemic sclerosis or interstitial lung disease (Mozaffarian et al, 2008; Roberts et al, 1986; Sempowski et al, 1994; Zhu et al, 1999)
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 interferong (IFN-g), STAT1, or RAG-1. IFN-g and STAT1 signaling disrupted the turnover of extracellular matrix by metalloproteases. 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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