title: STAT3 activity is necessary and sufficient for the development of immune-mediated myocarditis in mice and promotes progression to dilated cardiomyopathy.
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.
authors: Department of Biotechnology and Life Sciences, Molecular Biotechnology Center, University of Torino, Torino, Italy. annalisa.camporeale@unito.it
authors: Annalisa
authors: A
authors: Camporeale
authors: Francesca
authors: F
authors: Marino
authors: Anna
authors: A
authors: Papageorgiou
authors: Paolo
authors: P
authors: Carai
authors: Sara
authors: S
authors: Fornero
authors: Steven
authors: S
authors: Fletcher
authors: Brent D G
authors: BD
authors: Page
authors: Patrick
authors: P
authors: Gunning
authors: Marco
authors: M
authors: Forni
authors: Roberto
authors: R
authors: Chiarle
authors: Mara
authors: M
authors: Morello
authors: Ole
authors: O
authors: Jensen
authors: Renzo
authors: R
authors: Levi
authors: Stephane
authors: S
authors: Heymans
authors: Valeria
authors: V
authors: Poli
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000382:microbiology; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000276:immunology*; D003176:Complement C3 / Q000276:immunology; D018450:Disease Progression; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D008099:Liver / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009205:Myocarditis / Q000235:genetics / Q000276:immunology*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology
chemical_list: D003176:Complement C3; D015850:Interleukin-6; D050796:STAT3 Transcription Factor