These authors contributed equally to this work.
Genetic partitioning of interleukin-6 signalling in mice dissociates Stat3 from Smad3-mediated lung fibrosis
Version of Record online: 8 JUN 2012
Copyright © 2012 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
EMBO Molecular Medicine
Volume 4, Issue 9, pages 939–951, September 2012
How to Cite
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. and Mutsaers, S. E. (2012), Genetic partitioning of interleukin-6 signalling in mice dissociates Stat3 from Smad3-mediated lung fibrosis. EMBO Mol Med, 4: 939–951. doi: 10.1002/emmm.201100604
- Issue online: 4 SEP 2012
- Version of Record online: 8 JUN 2012
- Manuscript Accepted: 9 MAY 2012
- Manuscript Revised: 16 APR 2012
- Manuscript Received: 18 JAN 2011
- Operational Infrastructure Support Program provided by the Victorian Government, the National Health and Medical Research Council (NHMRC) of Australia. Grant Numbers: 3030137, 458703
- interleukin 6;
- pulmonary fibrosis;
- transforming growth factor beta
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.