STAT3 activity is necessary and sufficient for the development of immune‐mediated myocarditis in mice and promotes progression to dilated cardiomyopathy

EMBO Molecular Medicine

Annalisa Camporeale⁷  Francesca Marino⁵  Anna Papageorgiou⁸  Paolo Carai⁸  Sara Fornero⁴  Steven Fletcher⁶  Brent D. G. Page⁶  Patrick Gunning⁶  Marco Forni⁵  Roberto Chiarle²  Mara Morello¹  Ole Jensen³  Renzo Levi⁴  Stephane Heymans⁸ 

[1] Department of Medical Science, University of Torino, Torino, Italy;Department of Biomedical Sciences and Human Oncology and CERMS, University of Torino, Torino, Italy;Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense M, Denmark;Department of Life Sciences and Systems Biology, University of Torino, Torino, Italy;Department of Biotechnology and Life Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy;Department of Chemistry, University of Toronto, Mississauga Road North, Mississauga, ON, Canada;E-mail address: 关键词: complement C3;    experimental autoimmune myocarditis;    interleukin‐6;    immune‐mediated myocarditis;    STAT3;   

DOI  :  10.1002/emmm.201201876

来源: Wiley

【 摘 要 】

Abstract

Myocarditis, often triggered by viral infection, may lead to heart auto-immunity and dilated cardiomyopathy. What determines the switch between disease resolution and progression is however incompletely understood. We show that pharmacological inhibition of STAT3, the main mediator of IL-6 signalling and of Th17-cell differentiation, protects mice from the development of Experimental Auto-immune Myocarditis reducing liver production of the complement component C3, and can act therapeutically when administered at disease peak. Further, we demonstrate that STAT3 is sufficient when constitutively active for triggering the onset of immune-mediated myocarditis, involving enhanced complement C3 production and IL-6 signalling amplification in the liver. Disease development can be prevented by C3 depletion and IL-6 receptor neutralization. This appears to be relevant to disease pathogenesis in humans, since acute myocarditis patients display significantly elevated circulating IL-6 and C3 levels and activated heart STAT3. Thus, aberrant IL-6/STAT3-mediated induction of liver acute phase response genes including C3, which occurs as a consequence of pre-existing inflammatory conditions, might represent an important factor determining the degree of myocarditis and its clinical outcome.

【 授权许可】

CC BY   
Copyright © 2013 EMBO Molecular Medicine

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