Interleukin-6 Signaling Drives Fibrosis in Unresolved Inflammation

• Published in: Immunity (Cambridge, Mass.) Vol. 40; no. 1; pp. 40 - 50
• Main Authors: Fielding, Ceri A., Jones, Gareth W., McLoughlin, Rachel M., McLeod, Louise, Hammond, Victoria J., Uceda, Javier, Williams, Anwen S., Lambie, Mark, Foster, Thomas L., Liao, Chia-Te, Rice, Christopher M., Greenhill, Claire J., Colmont, Chantal S., Hams, Emily, Coles, Barbara, Kift-Morgan, Ann, Newton, Zarabeth, Craig, Katherine J., Williams, John D., Williams, Geraint T., Davies, Simon J., Humphreys, Ian R., O’Donnell, Valerie B., Taylor, Philip R., Jenkins, Brendan J., Topley, Nicholas, Jones, Simon A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16-01-2014; Elsevier Limited; Cell Press
• Subjects: Acute Disease; Adoptive Transfer; Animals; Cells, Cultured; Charitable foundations; Chronic Disease; Cytokines; Disease Models, Animal; Extracellular Matrix - immunology; Feedback, Physiological; Fibrosis; Humans; Interferon-gamma - genetics; Interferon-gamma - metabolism; Interleukin-6 - genetics; Interleukin-6 - immunology; Interleukin-6 - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Peritoneal dialysis; Peritoneum - pathology; Peritonitis - genetics; Peritonitis - pathology; Signal Transduction; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - metabolism; Th1 Cells - immunology; Th1 Cells - transplantation; Viral infections
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2013.10.022

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.
•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