Publication

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

Journal Paper/Review - Aug 1, 2007

PubMed
Doi

Citation
Reifenberg K, Münzel T, Wenzel P, Pieske B, Schmidt A, Kleinert H, Pautz A, Warger T, Rechtsteiner G, Yamamura K, Nusser P, Ott S, Becker C, Küpper I, Wiese E, Steige G, Torzewski M, Lehr H, Löhler J. Interferon-gamma induces chronic active myocarditis and cardiomyopathy in transgenic mice. Am J Pathol 2007; 171:463-72.
Type
Journal Paper/Review (English)
Journal
Am J Pathol 2007; 171
Publication Date
Aug 1, 2007
Issn Print
0002-9440
Pages
463-72
Brief description/objective

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-alpha is involved in the development of chronic heart failure, but a putative cardiotoxic potential of the proinflammatory cytokine interferon (IFN)-gamma remains primarily unknown. To investigate this issue we analyzed the cardiac phenotype of SAP-IFN-gamma transgenic mice, which constitutively express IFN-gamma in their livers and hence exhibit high circulating serum levels of this cytokine. SAP-IFN-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 IFN-gamma overexpression. IFN-gamma-mediated cardiotoxicity was associated with high-level cardiac transcription of the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-12 and the macrophage-attracting chemokines MCP1 and MIP1-alpha. Myotoxic IFN-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 IFN-gamma cardiotoxicity remains to be elucidated.