Lethal autoimmune myocarditis in interferon-gamma receptor-deficient mice - Enhanced disease severity by impaired inducible nitric oxide synthase induction

Background-Interferon-gamma (IFN-gamma) is an essential cytokine in the reg ulation of inflammatory responses in autoimmune diseases. Little is known a bout its role in inflammatory heart disease. Methods and Results-We showed that IFN-gamma receptor-deficient mice (IFN-g ammaR(-/-)) on a BALB/c background immunized with a peptide derived from ca rdiac alpha -myosin heavy chain develop severe myocarditis with high mortal ity. Although myocarditis subsided in wild-type mice after 3 weeks, IFN-gam maR(-/-) mice showed persistent disease. The persistent inflammation was ac companied by vigorous in vitro CD4 T-cell responses and impaired inducible nitric oxide synthase expression, together with evidence of impaired nitric oxide production in IFN-gammaR(-/-) hearts. Treatment of wild-type mice wi th the nitric oxide synthetase inhibitor N-nitro-L-arginine-methyl-ester en hanced in vitro CD4 T-cell proliferation and prevented healing of myocardit is. Conclusions-Our data provide evidence that IFN-gamma protects mice fi om le thal autoimmune myocarditis by inducing the expression of inducible nitric oxide synthase followed by the downregulation of T-cell responses.