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Protects against Chronic Viral Myocarditis by Reducing Mast Cell Degranulation, Fibrosis, and the Profibrotic Cytokines Transforming Growth Factor-ß1, Interleukin-1ß, and Interleukin-4 in the Heart
From the Departments of Pathology* and Anesthesiology and Critical Care Medicine, and the W. Harry Feinstone Department of Molecular Microbiology and Immunology, the Johns Hopkins Medical Institutions, Baltimore, Maryland
Inflammatory fibrosis is a characteristic feature of myocarditis, dilated cardiomyopathy (DCM), and congestive heart failure. Th1-type immune responses, mediated by interleukin (IL)-12-induced interferon (IFN)-
, are believed to exacerbate autoimmune diseases including myocarditis. In this study, we examined the effect of IL-12Rß1 and IFN- deficiency on the development of chronic CB3-induced myocarditis using knockout mice. We found increased chronic CB3-induced myocarditis (14.1 to 43.1%, P < 0.001); pericarditis (1.5 to 7.6%, P < 0.001); fibrosis (9.7 to 27.4%, P < 0.05); and the profibrotic cytokines transforming growth factor-ß1, IL-1ß, and IL-4 in the hearts of IFN--deficient mice. All mice infected with CB3 developed DCM, but IFN--deficient mice developed a fibrous, adhesive pericarditis associated with increased numbers of degranulating mast cells (MCs) in the pericardium (26.6 to 45.9%, P < 0.01), increased histamine levels (716 to 1930 ng/g of heart, P < 0.01), and reduced survival (100 to 43%). In contrast, IL-12Rß1 deficiency did not significantly alter the development of chronic myocarditis. Thus, IFN- protects against the development of severe chronic myocarditis, pericarditis, and DCM after CB3 infection by reducing MC degranulation, fibrosis, and the profibrotic cytokines transforming growth factor-ß1, IL-1ß, and IL-4 in the heart.
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