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

Robert J.J. O'Donoghue, Darryl Andrew Knight, Carl D. Richards, Cecilia M. Prêle, Hui Ling Lau, Andrew G Jarnicki, Jessica Jones, Steven Bozinovski, Ross Vlahos, Stefan Thiem, Brent S McKenzie, Bo Wang, Philip Stumbles, Geoffrey J. Laurent, Robin J. McAnulty, Stefan Rose-John, Hong-Jian Zhu, Gary P. Anderson, Matthias R. Ernst, Steven E Mutsaers

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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.

Original languageEnglish
Pages (from-to)939-951
Number of pages13
JournalEMBO Molecular Medicine
Volume4
Issue number9
DOIs
Publication statusPublished - Sep 2012
Externally publishedYes

Keywords

  • Interleukin 6
  • Pulmonary fibrosis
  • Smad3
  • Stat3
  • Transforming growth factor beta

Cite this

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. (2012). Genetic partitioning of interleukin-6 signalling in mice dissociates Stat3 from Smad3-mediated lung fibrosis. EMBO Molecular Medicine, 4(9), 939-951. https://doi.org/10.1002/emmm.201100604