Interferon-γ induces chronic active myocarditis and cardiomyopathy in transgenic mice

Chronic heart failure is associated with an activation of the immune system characterized among other factors by the cardiac synthesis and serum expression of proinflammatory cytokines. There is unequivocal clinical and experimental evidence that the cytokine tumor necrosis factor-a is involved in the development of chronic heart failure, but a putative cardiotoxic potential of the proinflammatory cytokine interferon (IEFN)-gamma remains primarily unknown. To investigate this issue we analyzed the cardiac phenotype of SAP-IEFN-gamma transgenic mice, which constitutively express IEFN-gamma in their fivers and hence exhibit high circulating serum levels of this cytokine. SAPIFN-gamma mice spontaneously developed chronic active myocarditis, characterized by the infiltration of not only CD4(+) and CD8(+) T cells but also Mac2(+) (galectin 3(+)) macrophages and CD11c(+) dendritic cells, eventually culminating in cardiomyopathy. Echocardiographic analyses exhibited a left ventricular dilation and impaired systolic function induced by rFN-gamma over- expression. IFN-gamma-mediated cardiotoxicity was associated with high-level cardiac transcription of the proinflammatory cytokines tumor necrosis factor-a and interleukin-12 and the macrophage-attracting chemokines MCP1 and MIEP1-alpha. Myotoxic ILFN-gamma effects could not be detected in smooth or striated muscle tissue, suggesting cardiomyocellular specificity of the toxic IFN-gamma effect. The precise mechanism of rFN-gamma cardiotoxicity remains to be elucidated.