title: Interleukin-6 signaling drives fibrosis in unresolved inflammation.
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.
authors.affiliation: Cardiff Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Ceri A
authors.initials: CA
authors.lastname: Fielding
authors.affiliation: Cardiff Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Gareth W
authors.initials: GW
authors.lastname: Jones
authors.affiliation: Cardiff Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: McLoughlin
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Monash Institute for Medical Research, Monash University, Clayton, VIC 3168, Australia.
authors.forename: Louise
authors.initials: L
authors.lastname: McLeod
authors.affiliation: Cardiff Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Victoria J
authors.initials: VJ
authors.lastname: Hammond
authors.affiliation: Cardiff Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Javier
authors.initials: J
authors.lastname: Uceda
authors.affiliation: Cardiff Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Anwen S
authors.initials: AS
authors.lastname: Williams
authors.affiliation: Department of Nephrology, University Hospital of North Staffordshire and Institute for Science and Technology in Medicine, Keele University, Stoke-on-Trent ST4 7QB, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Lambie
authors.affiliation: Cardiff Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Foster
authors.affiliation: Cardiff Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Chia-Te
authors.initials: CT
authors.lastname: Liao
authors.affiliation: Cardiff Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Rice
authors.affiliation: Cardiff Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Claire J
authors.initials: CJ
authors.lastname: Greenhill
authors.affiliation: Cardiff Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Chantal S
authors.initials: CS
authors.lastname: Colmont
authors.affiliation: Cardiff Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Emily
authors.initials: E
authors.lastname: Hams
authors.affiliation: Cardiff Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Barbara
authors.initials: B
authors.lastname: Coles
authors.affiliation: Cardiff Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Ann
authors.initials: A
authors.lastname: Kift-Morgan
authors.affiliation: Cardiff Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Zarabeth
authors.initials: Z
authors.lastname: Newton
authors.affiliation: Institute of Nephrology, Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Katherine J
authors.initials: KJ
authors.lastname: Craig
authors.affiliation: Institute of Nephrology, Institute of Molecular and Experimental Medicine, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: John D
authors.initials: JD
authors.lastname: Williams
authors.affiliation: Section of Pathology, Institute of Cancer and Genetics, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Geraint T
authors.initials: GT
authors.lastname: Williams
authors.affiliation: Department of Nephrology, University Hospital of North Staffordshire and Institute for Science and Technology in Medicine, Keele University, Stoke-on-Trent ST4 7QB, UK.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Davies
authors.affiliation: Cardiff Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Ian R
authors.initials: IR
authors.lastname: Humphreys
authors.affiliation: Cardiff Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Valerie B
authors.initials: VB
authors.lastname: O'Donnell
authors.affiliation: Cardiff Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK.
authors.forename: Philip R
authors.initials: PR
authors.lastname: Taylor
authors.affiliation: Centre for Innate Immunity and Infectious Diseases, Monash Institute for Medical Research, Monash University, Clayton, VIC 3168, Australia.
authors.forename: Brendan J
authors.initials: BJ
authors.lastname: Jenkins
authors.affiliation: Cardiff Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK. Electronic address: topley@cf.ac.uk.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Topley
authors.affiliation: Cardiff Institute of Infection and Immunity, Cardiff University, School of Medicine, Heath Park, Cardiff CF14 4XN, UK. Electronic address: jonessa@cf.ac.uk.
authors.forename: Simon A
authors.initials: SA
authors.lastname: Jones
mesh_terms: D000208:Acute Disease; D019264:Adoptive Transfer; D000818:Animals; D002478:Cells, Cultured; D002908:Chronic Disease; D004195:Disease Models, Animal; D005109:Extracellular Matrix / Q000276:immunology; D025461:Feedback, Physiological; D005355:Fibrosis; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010537:Peritoneum / Q000473:pathology*; D010538:Peritonitis / Q000235:genetics* / Q000473:pathology*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018417:Th1 Cells / Q000276:immunology* / Q000637:transplantation
chemical_list: D015850:Interleukin-6; D050794:STAT1 Transcription Factor; D007371:Interferon-gamma