Interleukin-6 signaling drives fibrosis in unresolved inflammation

Ceri A. Fielding; Gareth Wyn Jones; Rachel Mary McLoughlin; Louise McLeod; Victoria J. Hammond; Javier Uceda; Anwen Sian Williams; Mark Lambie; Thomas L. Foster; Chia-Te Liao; Christopher M. Rice; Claire J. Greenhill; Chantal Sophie Colmont; Emily Hams; Barbara Coles; Ann Kift-Morgan; Zarabeth Newton; Katherine J. Craig; John David Williams; Geraint Trefor Williams; Simon J. Davies; Ian R. Humphreys; Valerie Bridget O'Donnell; Philip Russel Taylor; Brendan J. Jenkins; Nicholas Topley; Simon Arnett Jones

doi:10.1016/j.immuni.2013.10.022

Interleukin-6 signaling drives fibrosis in unresolved inflammation

Ceri A. Fielding, Gareth Wyn Jones, Rachel Mary McLoughlin, Louise McLeod, Victoria J. Hammond, Javier Uceda, Anwen Sian Williams, Mark Lambie, Thomas L. Foster, Chia-Te Liao, Christopher M. Rice, Claire J. Greenhill, Chantal Sophie Colmont, Emily Hams, Barbara Coles, Ann Kift-Morgan, Zarabeth Newton, Katherine J. Craig, John David Williams, Geraint Trefor WilliamsSimon J. Davies, Ian R. Humphreys, Valerie Bridget O'Donnell, Philip Russel Taylor, Brendan J. Jenkins, Nicholas Topley, Simon Arnett Jones

School of Cellular and Molecular Medicine

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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-gamma (IFN-gamma), STAT1, or RAG-1. Here, IFN-gamma 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.

Original language	English
Pages (from-to)	40-50
Number of pages	11
Journal	Immunity
Volume	40
Issue number	1
Early online date	9 Jan 2014
DOIs	https://doi.org/10.1016/j.immuni.2013.10.022
Publication status	Published - 16 Jan 2014

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10.1016/j.immuni.2013.10.022

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Dr Gareth Jones
- g.jones@bristol.ac.uk
- School of Cellular and Molecular Medicine - Senior Lecturer
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Fielding, C. A., Jones, G. W., McLoughlin, R. M., McLeod, L., Hammond, V. J., Uceda, J., Williams, A. S., Lambie, M., Foster, T. L., Liao, C-T., Rice, C. M., Greenhill, C. J., Colmont, C. S., Hams, E., Coles, B., Kift-Morgan, A., Newton, Z., Craig, K. J., Williams, J. D., ... Jones, S. A. (2014). Interleukin-6 signaling drives fibrosis in unresolved inflammation. Immunity, 40(1), 40-50. https://doi.org/10.1016/j.immuni.2013.10.022

Fielding, Ceri A. ; Jones, Gareth Wyn ; McLoughlin, Rachel Mary ; McLeod, Louise ; Hammond, Victoria J. ; Uceda, Javier ; Williams, Anwen Sian ; Lambie, Mark ; Foster, Thomas L. ; Liao, Chia-Te ; Rice, Christopher M. ; Greenhill, Claire J. ; Colmont, Chantal Sophie ; Hams, Emily ; Coles, Barbara ; Kift-Morgan, Ann ; Newton, Zarabeth ; Craig, Katherine J. ; Williams, John David ; Williams, Geraint Trefor ; Davies, Simon J. ; Humphreys, Ian R. ; O'Donnell, Valerie Bridget ; Taylor, Philip Russel ; Jenkins, Brendan J. ; Topley, Nicholas ; Jones, Simon Arnett. / Interleukin-6 signaling drives fibrosis in unresolved inflammation. In: Immunity. 2014 ; Vol. 40, No. 1. pp. 40-50.

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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-gamma (IFN-gamma), STAT1, or RAG-1. Here, IFN-gamma 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.",

author = "Fielding, {Ceri A.} and Jones, {Gareth Wyn} and McLoughlin, {Rachel Mary} and Louise McLeod and Hammond, {Victoria J.} and Javier Uceda and Williams, {Anwen Sian} and Mark Lambie and Foster, {Thomas L.} and Chia-Te Liao and Rice, {Christopher M.} and Greenhill, {Claire J.} and Colmont, {Chantal Sophie} and Emily Hams and Barbara Coles and Ann Kift-Morgan and Zarabeth Newton and Craig, {Katherine J.} and Williams, {John David} and Williams, {Geraint Trefor} and Davies, {Simon J.} and Humphreys, {Ian R.} and O'Donnell, {Valerie Bridget} and Taylor, {Philip Russel} and Jenkins, {Brendan J.} and Nicholas Topley and Jones, {Simon Arnett}",

year = "2014",

month = jan,

day = "16",

doi = "10.1016/j.immuni.2013.10.022",

language = "English",

volume = "40",

pages = "40--50",

journal = "Immunity",

issn = "1074-7613",

publisher = "Cell Press",

number = "1",

}

Fielding, CA, Jones, GW, McLoughlin, RM, McLeod, L, Hammond, VJ, Uceda, J, Williams, AS, Lambie, M, Foster, TL, Liao, C-T, Rice, CM, Greenhill, CJ, Colmont, CS, Hams, E, Coles, B, Kift-Morgan, A, Newton, Z, Craig, KJ, Williams, JD, Williams, GT, Davies, SJ, Humphreys, IR, O'Donnell, VB, Taylor, PR, Jenkins, BJ, Topley, N & Jones, SA 2014, 'Interleukin-6 signaling drives fibrosis in unresolved inflammation', Immunity, vol. 40, no. 1, pp. 40-50. https://doi.org/10.1016/j.immuni.2013.10.022

Interleukin-6 signaling drives fibrosis in unresolved inflammation. / Fielding, Ceri A.; Jones, Gareth Wyn; McLoughlin, Rachel Mary; McLeod, Louise; Hammond, Victoria J.; Uceda, Javier; Williams, Anwen Sian; Lambie, Mark; Foster, Thomas L.; Liao, Chia-Te; Rice, Christopher M.; Greenhill, Claire J.; Colmont, Chantal Sophie; Hams, Emily; Coles, Barbara; Kift-Morgan, Ann; Newton, Zarabeth; Craig, Katherine J.; Williams, John David; Williams, Geraint Trefor; Davies, Simon J.; Humphreys, Ian R.; O'Donnell, Valerie Bridget; Taylor, Philip Russel; Jenkins, Brendan J.; Topley, Nicholas; Jones, Simon Arnett.

In: Immunity, Vol. 40, No. 1, 16.01.2014, p. 40-50.

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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T1 - Interleukin-6 signaling drives fibrosis in unresolved inflammation

AU - Fielding, Ceri A.

AU - Jones, Gareth Wyn

AU - McLoughlin, Rachel Mary

AU - McLeod, Louise

AU - Hammond, Victoria J.

AU - Uceda, Javier

AU - Williams, Anwen Sian

AU - Lambie, Mark

AU - Foster, Thomas L.

AU - Liao, Chia-Te

AU - Rice, Christopher M.

AU - Greenhill, Claire J.

AU - Colmont, Chantal Sophie

AU - Hams, Emily

AU - Coles, Barbara

AU - Kift-Morgan, Ann

AU - Newton, Zarabeth

AU - Craig, Katherine J.

AU - Williams, John David

AU - Williams, Geraint Trefor

AU - Davies, Simon J.

AU - Humphreys, Ian R.

AU - O'Donnell, Valerie Bridget

AU - Taylor, Philip Russel

AU - Jenkins, Brendan J.

AU - Topley, Nicholas

AU - Jones, Simon Arnett

PY - 2014/1/16

Y1 - 2014/1/16

N2 - 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-gamma (IFN-gamma), STAT1, or RAG-1. Here, IFN-gamma 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.

AB - 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-gamma (IFN-gamma), STAT1, or RAG-1. Here, IFN-gamma 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.

UR - http://orca.cf.ac.uk/61183/

U2 - 10.1016/j.immuni.2013.10.022

DO - 10.1016/j.immuni.2013.10.022

M3 - Article (Academic Journal)

C2 - 24412616

VL - 40

SP - 40

EP - 50

JO - Immunity

JF - Immunity

SN - 1074-7613

IS - 1

ER -

Interleukin-6 signaling drives fibrosis in unresolved inflammation

Abstract

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Dr Gareth Jones

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