Published online before print June 7, 2007

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(American Journal of Pathology. 2007;171:463-472.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060906

Interferon- Induces Chronic Active Myocarditis and Cardiomyopathy in Transgenic Mice

Kurt Reifenberg^*, Hans-Anton Lehr, Michael Torzewski, Gisela Steige^*, Elena Wiese^*, Ines Küpper^*, Christoph Becker, Sibylle Ott^¶, Petra Nusser^¶, Ken-Ichi Yamamura^||, Gerd Rechtsteiner^**, Tobias Warger^**, Andrea Pautz, Hartmut Kleinert, Albrecht Schmidt, Burkert Pieske, Philip Wenzel, Thomas Münzel and Jürgen Löhler^¶¶

From the Central Laboratory Animal Facility,^* the Institute of Clinical Chemistry and Laboratory Medicine, the First Medical Clinic, the Institute of Immunology,^** the Institute of Pharmacology, and the Second Medical Clinic, Johannes Gutenberg-University, Mainz, Germany; the Department of Cardiology and Pneumology, University of Goettingen, Goettingen, Germany; Laboratory Animal Research Unit,^¶ University of Ulm, Ulm, Germany; Heinrich Pette Institute for Experimental Virology and Immunology,^¶¶ Hamburg, Germany; Institut Universitaire de Pathologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; and the Institute of Molecular Embryology and Genetics,|| Kumamoto, Japan

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- is involved in the development of chronic heart failure, but a putative cardiotoxic potential of the proinflammatory cytokine interferon (IFN)- remains primarily unknown. To investigate this issue we analyzed the cardiac phenotype of SAP-IFN- transgenic mice, which constitutively express IFN- in their livers and hence exhibit high circulating serum levels of this cytokine. SAP-IFN- 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- overexpression. IFN--mediated cardiotoxicity was associated with high-level cardiac transcription of the proinflammatory cytokines tumor necrosis factor- and interleukin-12 and the macrophage-attracting chemokines MCP1 and MIP1-. Myotoxic IFN- effects could not be detected in smooth or striated muscle tissue, suggesting cardiomyocellular specificity of the toxic IFN- effect. The precise mechanism of IFN- cardiotoxicity remains to be elucidated.

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