Genetic partitioning of interleukin-6 signalling in mice dissociates Stat3 from Smad3-mediated lung fibrosis

R.J.J. O'Donoghue; D.A. Knight; C.D. Richards; C.M. Prêle; H.L. Lau; A.G. Jarnicki; J. Jones; S. Bozinovski; R. Vlahos; S. Thiem; B.S. McKenzie; B. Wang; P.A. Stumbles; G.J. Laurent; R.J. McAnulty; S. Rose-John; H.J. Zhu; G.P. Anderson; M.R. Ernst; S.E. Mutsaers

doi:10.1002/emmm.201100604

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Genetic partitioning of interleukin-6 signalling in mice dissociates Stat3 from Smad3-mediated lung fibrosis

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Genetic partitioning of interleukin-6 signalling in mice dissociates Stat3 from Smad3-mediated lung fibrosis

R.J.J. O'Donoghue, D.A. Knight, C.D. Richards, C.M. Prêle, H.L. Lau, A.G. Jarnicki, J. Jones, S. Bozinovski, R. Vlahos, S. Thiem, …

EMBO Molecular Medicine, Vol.4(9), pp.939-951

2012

DOI: https://doi.org/10.1002/emmm.201100604

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Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal disease that is unresponsive to current therapies and characterized by excessive collagen deposition and subsequent fibrosis. While inflammatory cytokines, including interleukin (IL)-6, are elevated in IPF, the molecular mechanisms that underlie this disease are incompletely understood, although the development of fibrosis is believed to depend on canonical transforming growth factor (TGF)-β signalling. We examined bleomycin-induced inflammation and fibrosis in mice carrying a mutation in the shared IL-6 family receptor gp130. Using genetic complementation, we directly correlate the extent of IL-6-mediated, excessive Stat3 activity with inflammatory infiltrates in the lung and the severity of fibrosis in corresponding gp130757F mice. The extent of fibrosis was attenuated in B lymphocyte-deficient gp130757F;µMT−/− compound mutant mice, but fibrosis still occurred in their Smad3−/− counterparts consistent with the capacity of excessive Stat3 activity to induce collagen 1α1 gene transcription independently of canonical TGF-β/Smad3 signalling. These findings are of therapeutic relevance, since we confirmed abundant STAT3 activation in fibrotic lungs from IPF patients and showed that genetic reduction of Stat3 protected mice from bleomycin-induced lung fibrosis.

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Title: Genetic partitioning of interleukin-6 signalling in mice dissociates Stat3 from Smad3-mediated lung fibrosis
Authors/Creators: R.J.J. O'Donoghue (Author/Creator) - Ludwig Institute for Cancer Research, Melbourne – Parkville Branch, Parkville, Victoria, Australia
D.A. Knight (Author/Creator) - Lung Institute
C.D. Richards (Author/Creator) - McMaster University
C.M. Prêle (Author/Creator) - The University of Western Australia
H.L. Lau (Author/Creator) - The University of Western Australia
A.G. Jarnicki (Author/Creator) - Ludwig Institute for Cancer Research, Melbourne-Parkville Branch, Parkville, Victoria, Australia
J. Jones (Author/Creator) - The University of Melbourne
S. Bozinovski (Author/Creator) - The University of Melbourne
R. Vlahos (Author/Creator) - The University of Melbourne
S. Thiem (Author/Creator) - Ludwig Institute for Cancer Research, Melbourne-Parkville Branch, Parkville, Victoria, Australia
B.S. McKenzie (Author/Creator) - CSL Ltd, Bio21 Institute, Parkville, Victoria, Australia
B. Wang (Author/Creator) - The University of Melbourne
P.A. Stumbles (Author/Creator) - The Kids Research Institute Australia
G.J. Laurent (Author/Creator) - UCL Australia
R.J. McAnulty (Author/Creator) - University College London
S. Rose-John (Author/Creator) - Christian-Albrechts-Universität zu Kiel
H.J. Zhu (Author/Creator) - The University of Melbourne
G.P. Anderson (Author/Creator) - The University of Melbourne
M.R. Ernst (Author/Creator) - Ludwig Institute for Cancer Research, Melbourne-Parkville Branch, Parkville, Victoria, Australia
S.E. Mutsaers (Author/Creator) - The University of Western Australia
Publication Details: EMBO Molecular Medicine, Vol.4(9), pp.939-951
Publisher: Published by John Wiley and Sons, Ltd on behalf of EMBO.
Identifiers: 991005541573907891
Copyright: © 2012 The Authors
Murdoch Affiliation: Other Affiliations
Language: English
Resource Type: Journal article
Note: This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License (CC BY-NC 3.0), which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

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Collaboration types: Industry collaboration; Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.208 Vasculitis & Autoimmune Disorders; 1.208.1262 Idiopathic Pulmonary Fibrosis
Web Of Science research areas: Medicine, Research & Experimental
ESI research areas: Clinical Medicine