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

O&#39;Donoghue, RJ; Knight, DA; Richards, CD; Prele, CM; Lau, HL; Jarnicki, AG; Jones, J; Bozinovski, S; Vlahos, R; Thiem, S; McKenzie, BS; Wang, B; Stumbles, P; Laurent, GJ; McAnulty, RJ; Rose-John, S; Zhu, HJ; Anderson, GP; Ernst, MR; Mutsaers, SE

Author(s): O'Donoghue, RJ; Knight, DA; Richards, CD; Prele, CM; Lau, HL; Jarnicki, AG; Jones, J; Bozinovski, S; Vlahos, R; Thiem, S; McKenzie, BS; Wang, B; Stumbles, P; Laurent, GJ; McAnulty, RJ; Rose-John, S; Zhu, HJ; Anderson, GP; Ernst, MR; Mutsaers, SE;
Details: Publication Year 2012-09,Volume 4,Issue #9,Page 939-51
Journal Title: EMBO molecular medicine
Publication Type: Journal Article
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)-beta 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);microMT(-/-) compound mutant mice, but fibrosis still occurred in their Smad3(-/-) counterparts consistent with the capacity of excessive Stat3 activity to induce collagen 1alpha1 gene transcription independently of canonical TGF-beta/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.
Keywords: Interleukin 6Pulmonary FibrosisSmad3Stat3Transforming Growth Factor Beta
Publisher's Version: https://doi.org/10.1002/emmm.201100604
Open Access at Publisher's Site: http://embomolmed.embopress.org/content/4/9/939
Terms of Use/Rights Notice: Copyright© 2013 European Molecular Biology Organization 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.

Creation Date: 2014-01-20 09:37:37