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

Authors

  • Robert J. J. O'Donoghue,

    1. Ludwig Institute for Cancer Research, Melbourne – Parkville Branch, Parkville, Victoria, Australia
    2. Centre for Asthma Allergy and Respiratory Research, School of Medicine and Pharmacology, University of Western Australia, Nedlands, Western Australia, Australia
    3. Lung Institute of Western Australia, Nedlands, Western Australia, Australia
    4. Departments of Pharmacology and Medicine, University of Melbourne, Melbourne, Victoria, Australia
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  • Darryl A. Knight,

    1. UBC James Hogg Research Centre, Heart+Lung Institute, Vancouver, BC, Canada
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  • Carl D. Richards,

    1. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada
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  • Cecilia M. Prêle,

    1. Centre for Asthma Allergy and Respiratory Research, School of Medicine and Pharmacology, University of Western Australia, Nedlands, Western Australia, Australia
    2. Lung Institute of Western Australia, Nedlands, Western Australia, Australia
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  • Hui Ling Lau,

    1. Centre for Asthma Allergy and Respiratory Research, School of Medicine and Pharmacology, University of Western Australia, Nedlands, Western Australia, Australia
    2. Lung Institute of Western Australia, Nedlands, Western Australia, Australia
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  • Andrew G. Jarnicki,

    1. Ludwig Institute for Cancer Research, Melbourne – Parkville Branch, Parkville, Victoria, Australia
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  • Jessica Jones,

    1. Departments of Pharmacology and Medicine, University of Melbourne, Melbourne, Victoria, Australia
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  • Steven Bozinovski,

    1. Departments of Pharmacology and Medicine, University of Melbourne, Melbourne, Victoria, Australia
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  • Ross Vlahos,

    1. Departments of Pharmacology and Medicine, University of Melbourne, Melbourne, Victoria, Australia
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  • Stefan Thiem,

    1. Ludwig Institute for Cancer Research, Melbourne – Parkville Branch, Parkville, Victoria, Australia
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  • Brent S. McKenzie,

    1. CSL Ltd, Bio21 Institute, Parkville, Victoria, Australia
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  • Bo Wang,

    1. Department of Surgery, University of Melbourne, Melbourne, Victoria, Australia
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  • Philip Stumbles,

    1. Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, Western Australia, Australia
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  • Geoffrey J. Laurent,

    1. Centre for Respiratory Research, Rayne Institute, Royal Free and University College London, London, UK
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  • Robin J. McAnulty,

    1. Centre for Respiratory Research, Rayne Institute, Royal Free and University College London, London, UK
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  • Stefan Rose-John,

    1. Department of Biochemistry, Christian-Albrechts-Universität zu Kiel, Kiel, Germany
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  • Hong Jian Zhu,

    1. Department of Surgery, University of Melbourne, Melbourne, Victoria, Australia
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  • Gary P. Anderson,

    1. Departments of Pharmacology and Medicine, University of Melbourne, Melbourne, Victoria, Australia
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  • Matthias R. Ernst,

    Corresponding author
    1. Ludwig Institute for Cancer Research, Melbourne – Parkville Branch, Parkville, Victoria, Australia
    • Matthias R. Ernst, Tel: +61 3 9341 3155; Fax: +61 3 9341 3104

      Steven E. Mutsaers, Tel: +61 8 9346 7948; Fax: +61 8 9346 4159

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    • These authors contributed equally to this work.

  • Steven E. Mutsaers

    Corresponding author
    1. Centre for Asthma Allergy and Respiratory Research, School of Medicine and Pharmacology, University of Western Australia, Nedlands, Western Australia, Australia
    2. Lung Institute of Western Australia, Nedlands, Western Australia, Australia
    3. PathWest Laboratory Medicine WA, Nedlands, Western Australia, Australia
    • Matthias R. Ernst, Tel: +61 3 9341 3155; Fax: +61 3 9341 3104

      Steven E. Mutsaers, Tel: +61 8 9346 7948; Fax: +61 8 9346 4159

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    • These authors contributed equally to this work.


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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