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Cited by 152Interstitial Lung Diseases and Idiopathic Pulmonary FibrosisTGF-β signaling in diseasesCytokine Signaling Pathways and Interactions

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

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O'Donoghue, Robert J. J., Knight, Darryl A., Richards, Carl D., Prêle, Cecilia M., Lau, Hui Ling, Jarnicki, Andrew G., Jones, Jessica, Bozinovski, Steven +12 more·2012·EMBO Molecular Medicine
DOI 10.1002/emmm.201100604PMC PMC3491826
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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 gp130(757F) mice. The extent of fibrosis was attenuated in B lymphocyte-deficient gp130(757F);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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  • Genetic and pharmacological inhibition of STAT3 signaling suppresses fibrosis in many animal models, including lung fibrosis where STAT3 haploinsufficiency eliminated increased lung collagen in bleomycin-treated mice.

    “Genetic and pharmacological inhibition of STAT3 signaling has been shown to suppress fibrosis in many animal models, including models of lung fibrosis, in which haploinsufficiency of STAT3 eliminated the increase in lung collagen (hydroxproline) content in bleomycin-treated mice”

    From Targeting Janus Kinases and Signal Transducer and Activator of Transcription 3 To Treat Inflammation, Fibrosis, and Cancer: Rationale, Progress, and Caution (2020) · cites this paper as O’Donoghue et al., 2012

    The Results section, ‘Genetic restriction of Stat3 signalling ameliorates the fibrotic response in bleomycin-challenged mice’ (page unavailable), reports that Stat3+/− mice were completely protected from bleomycin-induced lung collagen deposition; Figure 6 identifies the collagen measure as lung hydroxyproline content. The paper supports this genetic lung-fibrosis example, but the cited passages do not establish that pharmacological STAT3 inhibition suppresses fibrosis across many animal models. (LLM, conf=0.86)

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Authors
O'Donoghue, R. J. J., Knight, D. A., Richards, C. D., Prêle, C. M., Lau, H. L., Jarnicki, A. G., Jones, J., Bozinovski, S., Vlahos, R., Thiem, S., McKenzie, B. S., Wang, B., Stumbles, P., Laurent, G. J., McAnulty, R. J., Rose‐John, S., Zhu, H. J., Anderson, G. P., Ernst, M. R., & Mutsaers, S. E.
Affiliations
  • University of British Columbia (CA)
  • McMaster University (CA)
  • The University of Western Australia (AU)
  • Ludwig Cancer Research (BE)
  • The University of Melbourne (AU)
  • CSL (Australia) (AU)
  • The Kids Research Institute Australia (AU)
  • The Royal Free Hospital (GB)
  • Christian-Albrechts-Universität zu Kiel (DE)
Corresponding author
  • Ernst, Matthias R.
  • Mutsaers, Steven E.
ORCID
Venue
EMBO Molecular Medicine
Publisher
Springer Science and Business Media LLC
Published
2012-06-08
Volume
4
Issue
9
Pages
939-951
ISSN
  • 1757-4676 (ISSN-L)
  • 1757-4684
DOI
10.1002/emmm.201100604
PMC
PMC3491826
OpenAlex
W2103759210
Cited by
152
References
53
Citations by year
2026: 5 · 2025: 5 · 2024: 12 · 2023: 14 · 2022: 22 · 2021: 8 · 2020: 14 · 2019: 13 · 2018: 11 · 2017: 10 · 2016: 10 · 2015: 7 · 2014: 9 · 2013: 10 · 2012: 2
FWCI
7.22
Type
journal article
Language
en
Open access
Licence
Locations
  • EMBO Molecular Medicine (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • UWA Profiles and Research Repository (UWA) (publishedVersion, other-oa)
  • PubMed (publishedVersion)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
  • Murdoch University Research Portal (submittedVersion)
  • RMIT Research Repository (RMIT University Library) (submittedVersion, other-oa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Figshare (submittedVersion, cc-by-nc)
Funders
Operational Infrastructure Support Program provided by the Victorian Government, the National Health and Medical Research Council (NHMRC) of Australia (3030137, 458703)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Keywords
idiopathic pulmonary fibrosis, STAT3, Smad3, TGF-beta signaling, gp130, bleomycin-induced lung fibrosis, B lymphocyte deficiency, gene complementation, lung inflammation, collagen deposition
MeSH terms
Animals, Bleomycin, Genetic Complementation Test, Male, Mice, Inbred C57BL, Pulmonary Fibrosis, Interleukin-6, Mice, Knockout, STAT3 Transcription Factor, Cytokine Receptor gp130, Mice, Smad3 Protein

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