[PDF][PDF] Interleukin-6 signaling drives fibrosis in unresolved inflammation

CA Fielding, GW Jones, RM McLoughlin, L McLeod… - Immunity, 2014 - cell.com
CA Fielding, GW Jones, RM McLoughlin, L McLeod, VJ Hammond, J Uceda, AS Williams…
Immunity, 2014cell.com
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 …
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.
cell.com