Neutralization of endogenous tumor necrosis factor ameliorates the severity of myosin-induced myocarditis.
Tumor necrosis factor (TNF) and interferon gamma (IFN-gamma) are pluripotent cytokines and have multiple functions during the inflammatory response. Using a murine model of autoimmune myocarditis, we studied the role of TNF and IFN-gamma in myocardial inflammation. Neutralizing monoclonal antibodies against TNF-alpha/beta and IFN-gamma were administered to myosin-immunized A/J mice to assess the effect on the severity of myocardial inflammation. Anti-TNF treatment significantly reduced the severity of myocarditis compared with rat immunoglobulin G or saline controls (p less than 0.0007) when given before myosin immunization. Myosin-specific lymph node T-cell proliferation studies showed no difference in the proliferative response between the anti-TNF-treated mice and controls. Administration of anti-TNF to mice after myosin immunization had no effect on the severity of inflammation. This suggests that TNF is an important mediator early in the pathogenesis of myocardial inflammation in this model of myocarditis. Neutralization of IFN-gamma significantly increased the severity of myocarditis compared with rat immunoglobulin G and saline controls (p less than 0.0065), suggesting that IFN-gamma may function as an important regulatory cytokine early in the pathogenesis of myocardial inflammation. Understanding the functions of cytokines during the inflammatory response to myocardial injury may provide important information on possible methods to limit myocardial damage.
Smith
S C
SC
Department of Internal Medicine, Washington University School of Medicine, St. Louis, Mo 63110.
Allen
P M
PM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001327:Autoimmune Diseases / Q000276:immunology / Q000503:physiopathology* / Q000628:therapy; D007114:Immunization; D007074:Immunoglobulin G / Q000008:administration & dosage; D007371:Interferon-gamma / Q000276:immunology / Q000502:physiology*; D008297:Male; D051379:Mice; D009205:Myocarditis / Q000276:immunology / Q000503:physiopathology* / Q000628:therapy; D009218:Myosins; D051381:Rats; D012965:Sodium Chloride / Q000008:administration & dosage; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000502:physiology*
D000911:Antibodies, Monoclonal; D007074:Immunoglobulin G; D014409:Tumor Necrosis Factor-alpha; D012965:Sodium Chloride; D007371:Interferon-gamma; D009218:Myosins