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

Autor: Annalisa Camporeale, Francesca Marino, Anna Papageorgiou, Paolo Carai, Sara Fornero, Steven Fletcher, Brent D. G. Page, Patrick Gunning, Marco Forni, Roberto Chiarle, Mara Morello, Ole Jensen, Renzo Levi, Stephane Heymans, Valeria Poli
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Zdroj: EMBO Molecular Medicine, Vol 5, Iss 4, Pp 572-590 (2013)
Druh dokumentu: article
ISSN: 1757-4676
1757-4684
DOI: 10.1002/emmm.201201876
Popis: 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.
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