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Nat Commun. 2017 Oct 24;8(1):1130. doi: 10.1038/s41467-017-01236-6.

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

Author information

1
Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, 91054, Germany.
2
Institute of Rheumatology and Department of Rheumatology, First Faculty of Medicine, Charles University, Prague, 120 00, Czech Republic.
3
Department of Plastic and Hand Surgery and Laboratory for Tissue Engineering and Regenerative Medicine, University Hospital of Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, 91054, Germany.
4
Department of Orthopaedic Trauma Surgery, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nürnberg (FAU), Erlangen, 91054, Germany.
5
Center of Experimental Rheumatology and Zurich Center of Integrative Human Physiology, University Hospital Zurich, Zurich, 8091, Switzerland.
6
Department of Internal Medicine 3 - Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and University Hospital Erlangen, Erlangen, 91054, Germany. joerg.distler@uk-erlangen.de.

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 TGFβ-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 TGFβ. 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.

PMID:
29066712
PMCID:
PMC5654983
DOI:
10.1038/s41467-017-01236-6
[Indexed for MEDLINE]
Free PMC Article

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