Abstract
Background:
Interferon-gamma (IFN-gamma) is an essential cytokine in the regulation of inflammatory responses in autoimmune diseases. Little is known about its role in inflammatory heart disease.
Methods and results:
We showed that IFN-gamma receptor-deficient mice (IFN-gammaR(-/-)) on a BALB/c background immunized with a peptide derived from cardiac alpha-myosin heavy chain develop severe myocarditis with high mortality. Although myocarditis subsided in wild-type mice after 3 weeks, IFN-gammaR(-/-) mice showed persistent disease. The persistent inflammation was accompanied 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 with the nitric oxide synthetase inhibitor N:-nitro-l-arginine-methyl-ester enhanced in vitro CD4 T-cell proliferation and prevented healing of myocarditis.
Conclusions:
Our data provide evidence that IFN-gamma protects mice from lethal autoimmune myocarditis by inducing the expression of inducible nitric oxide synthase followed by the downregulation of T-cell responses.
MeSH terms
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Adjuvants, Immunologic / biosynthesis
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Animals
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Autoimmune Diseases / complications
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Autoimmune Diseases / enzymology*
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Autoimmune Diseases / genetics
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Autoimmune Diseases / immunology
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CD4-Positive T-Lymphocytes / cytology
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / immunology
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Cell Division / drug effects
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Dose-Response Relationship, Drug
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Enzyme Induction / genetics
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Enzyme Inhibitors / pharmacology
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Immunity, Cellular / drug effects
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Immunity, Cellular / genetics
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Immunity, Cellular / immunology
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Immunohistochemistry
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Inflammation / enzymology
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Inflammation / immunology
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Inflammation / pathology
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Interferon gamma Receptor
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Interferon-gamma / metabolism
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Interferon-gamma / pharmacology
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Mutant Strains
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Myocarditis / complications
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Myocarditis / enzymology*
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Myocarditis / genetics
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Myocarditis / immunology
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Myocardium / immunology
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Myocardium / pathology
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Myosin Heavy Chains / immunology
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NG-Nitroarginine Methyl Ester / pharmacology
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Nitric Oxide / biosynthesis
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Nitric Oxide Donors / pharmacology
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Nitric Oxide Synthase / antagonists & inhibitors
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Nitric Oxide Synthase / biosynthesis*
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Nitric Oxide Synthase / genetics
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Nitric Oxide Synthase Type II
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Receptors, Interferon / deficiency*
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Receptors, Interferon / genetics
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Severity of Illness Index
Substances
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Adjuvants, Immunologic
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Enzyme Inhibitors
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Nitric Oxide Donors
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Receptors, Interferon
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Nitric Oxide
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Interferon-gamma
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Nitric Oxide Synthase
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Nitric Oxide Synthase Type II
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Nos2 protein, mouse
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Myosin Heavy Chains
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NG-Nitroarginine Methyl Ester