Activation of STAT3 integrates common profibrotic pathways to promote fibroblast activation and tissue fibrosis

Chakraborty D, Sumova B, Mallano T, Chen CW, Distler A, Bergmann C, Ludolph I, Horch RE, Gelse K, Ramming A, Distler O, Schett G, Senolt L, Distler J (2017)

Publication Type: Journal article

Publication year: 2017

Journal

Nature Communications Nature Publishing Group: Nature Communications

Book Volume: 8

Pages Range: 1130

Journal Issue: 1

DOI: 10.1038/s41467-017-01236-6

Abstract

Signal transducer and activator of transcription 3 (STAT3) is phosphorylated by various kinases, several of which have been implicated in aberrant fibroblast activation in fibrotic diseases including systemic sclerosis (SSc). Here we show that profibrotic signals converge on STAT3 and that STAT3 may be an important molecular checkpoint for tissue fibrosis. STAT3 signaling is hyperactivated in SSc in a TGF?-dependent manner. Expression profiling and functional studies in vitro and in vivo demonstrate that STAT3 activation is mediated by the combined action of JAK, SRC, c-ABL, and JNK kinases. STAT3-deficient fibroblasts are less sensitive to the pro-fibrotic effects of TGF?. Fibroblast-specific knockout of STAT3, or its pharmacological inhibition, ameliorate skin fibrosis in experimental mouse models. STAT3 thus integrates several profibrotic signals and might be a core mediator of fibrosis. Considering that several STAT3 inhibitors are currently tested in clinical trials, STAT3 might be a candidate for molecular targeted therapies of SSc.

Authors with CRIS profile

Debomita Chakraborty Department of Medicine 3 – Rheumatology and Immunology Tatjana Mallano Department of Medicine 3 – Rheumatology and Immunology Ingo Ludolph Department of Plastic and Hand Surgery Raymund Horch Professur für Plastische Chirurgie und Handchirurgie Andreas Ramming Department of Medicine 3 – Rheumatology and Immunology Georg Schett Lehrstuhl für Innere Medizin III Jörg Distler Professur für Molekulare Mechanismen der Organfibrose

Involved external institutions

Universitätsspital Zürich (USZ) CH Switzerland (CH) Univerzita Karlova v Praze / Charles University in Prague CZ Czech Republic (CZ)

How to cite

APA:

Chakraborty, D., Sumova, B., Mallano, T., Chen, C.-W., Distler, A., Bergmann, C.,... Distler, J. (2017). Activation of STAT3 integrates common profibrotic pathways to promote fibroblast activation and tissue fibrosis. Nature Communications, 8(1), 1130. https://dx.doi.org/10.1038/s41467-017-01236-6

MLA:

Chakraborty, Debomita, et al. "Activation of STAT3 integrates common profibrotic pathways to promote fibroblast activation and tissue fibrosis." Nature Communications 8.1 (2017): 1130.

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