Genetic partitioning of interleukin-6 signalling in mice dissociates Stat3 from Smad3-mediated lung fibrosis.
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.
Ludwig Institute for Cancer Research, Melbourne - Parkville Branch, Parkville, Victoria, Australia.
Robert J J
RJ
O'Donoghue
Darryl A
DA
Knight
Carl D
CD
Richards
Cecilia M
CM
Prêle
Hui Ling
HL
Lau
Andrew G
AG
Jarnicki
Jessica
J
Jones
Steven
S
Bozinovski
Ross
R
Vlahos
Stefan
S
Thiem
Brent S
BS
McKenzie
Bo
B
Wang
Philip
P
Stumbles
Geoffrey J
GJ
Laurent
Robin J
RJ
McAnulty
Stefan
S
Rose-John
Hong Jian
HJ
Zhu
Gary P
GP
Anderson
Matthias R
MR
Ernst
Steven E
SE
Mutsaers
D000818:Animals; D001761:Bleomycin / Q000633:toxicity; D050822:Cytokine Receptor gp130 / Q000172:deficiency; D005816:Genetic Complementation Test; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000096:biosynthesis*; D051900:Smad3 Protein / Q000172:deficiency
D015850:Interleukin-6; D050796:STAT3 Transcription Factor; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; C494087:Stat3 protein, mouse; D001761:Bleomycin; D050822:Cytokine Receptor gp130