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 regulation of inflammatory responses in autoimmune diseases. Little is known about its role in inflammatory heart disease.


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.
Eriksson
U
U
Medical Intensive Care Unit, University Hospital, Basel, Switzerland. klinerr@usz.unizh.ch
Kurrer
M O
MO
Bingisser
R
R
Eugster
H P
HP
Saremaslani
P
P
Follath
F
F
Marsch
S
S
Widmer
U
U
D000276:Adjuvants, Immunologic / Q000096:biosynthesis; D000818:Animals; D001327:Autoimmune Diseases / Q000150:complications / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002455:Cell Division / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007111:Immunity, Cellular / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D007150:Immunohistochemistry; D007249:Inflammation / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D009205:Myocarditis / Q000150:complications / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D009206:Myocardium / Q000276:immunology / Q000473:pathology; D018995:Myosin Heavy Chains / Q000276:immunology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000096:biosynthesis; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D017471:Receptors, Interferon / Q000172:deficiency* / Q000235:genetics; D012720:Severity of Illness Index; D000096743:Interferon gamma Receptor
D000276:Adjuvants, Immunologic; D004791:Enzyme Inhibitors; D007371:Interferon-gamma; D018995:Myosin Heavy Chains; D019331:NG-Nitroarginine Methyl Ester; D009569:Nitric Oxide; D020030:Nitric Oxide Donors; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C496317:Nos2 protein, mouse