Interleukin-6 signaling drives fibrosis in unresolved inflammation

Ceri A Fielding, Gareth W Jones, Rachel M McLoughlin, Louise McLeod, Victoria J Hammond, Javier Uceda, Anwen S Williams, Mark Lambie, Thomas L Foster, Chia-Te Liao, Christopher M Rice, Claire J Greenhill, Chantal S Colmont, Emily Hams, Barbara Coles, Ann Kift-Morgan, Zarabeth Newton, Katherine J Craig, John D Williams, Geraint T Williams & 7 others Simon J Davies, Ian R Humphreys, Valerie B O'Donnell, Philip R Taylor, Brendan John Jenkins, Nicholas Topley, Simon A Jones

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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 languageEnglish
Pages (from-to)40 - 50
Number of pages11
JournalImmunity
Volume40
Issue number1
DOIs
Publication statusPublished - 2014

Cite this

Fielding, C. A., Jones, G. W., McLoughlin, R. M., McLeod, L., Hammond, V. J., Uceda, J., ... 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 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 John ; Topley, Nicholas ; Jones, Simon A. / 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 W} and McLoughlin, {Rachel M} and Louise McLeod and Hammond, {Victoria J} and Javier Uceda and Williams, {Anwen S} and Mark Lambie and Foster, {Thomas L} and Chia-Te Liao and Rice, {Christopher M} and Greenhill, {Claire J} and Colmont, {Chantal S} and Emily Hams and Barbara Coles and Ann Kift-Morgan and Zarabeth Newton and Craig, {Katherine J} and Williams, {John D} and Williams, {Geraint T} and Davies, {Simon J} and Humphreys, {Ian R} and O'Donnell, {Valerie B} and Taylor, {Philip R} and Jenkins, {Brendan John} and Nicholas Topley and Jones, {Simon A}",
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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 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 John; Topley, Nicholas; Jones, Simon A.

In: Immunity, Vol. 40, No. 1, 2014, p. 40 - 50.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Interleukin-6 signaling drives fibrosis in unresolved inflammation

AU - Fielding, Ceri A

AU - Jones, Gareth W

AU - McLoughlin, Rachel M

AU - McLeod, Louise

AU - Hammond, Victoria J

AU - Uceda, Javier

AU - Williams, Anwen S

AU - Lambie, Mark

AU - Foster, Thomas L

AU - Liao, Chia-Te

AU - Rice, Christopher M

AU - Greenhill, Claire J

AU - Colmont, Chantal S

AU - Hams, Emily

AU - Coles, Barbara

AU - Kift-Morgan, Ann

AU - Newton, Zarabeth

AU - Craig, Katherine J

AU - Williams, John D

AU - Williams, Geraint T

AU - Davies, Simon J

AU - Humphreys, Ian R

AU - O'Donnell, Valerie B

AU - Taylor, Philip R

AU - Jenkins, Brendan John

AU - Topley, Nicholas

AU - Jones, Simon A

PY - 2014

Y1 - 2014

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://www.sciencedirect.com/science/article/pii/S107476131300561X

U2 - 10.1016/j.immuni.2013.10.022

DO - 10.1016/j.immuni.2013.10.022

M3 - Article

VL - 40

SP - 40

EP - 50

JO - Immunity

JF - Immunity

SN - 1074-7613

IS - 1

ER -

Fielding CA, Jones GW, McLoughlin RM, McLeod L, Hammond VJ, Uceda J et al. Interleukin-6 signaling drives fibrosis in unresolved inflammation. Immunity. 2014;40(1):40 - 50. https://doi.org/10.1016/j.immuni.2013.10.022