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(American Journal of Pathology. 2006;169:2085-2093.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.060350

Sustained Nitric Oxide Synthesis Contributes to Immunopathology in Ongoing Myocarditis Attributable to Interleukin-10 Disorders

Gudrun Szalay, Martina Sauter, Joachim Hald, Andreas Weinzierl, Reinhard Kandolf and Karin Klingel

From the Department of Molecular Pathology, Institute for Pathology, University Hospital Tübingen, Tübingen, Germany

Ongoing coxsackievirus B3 (CVB3) myocarditis is characterized by persistence of viral RNA and chronic inflammation primarily mediated by macrophages and T cells. Activated macrophages produce anti-viral effector molecules comprising reactive nitrogen intermediates; however, reactive nitrogen intermediates also contribute to host tissue damage. Controlled activation of macrophages depends on interferon (IFN)-{gamma} and interleukin (IL)-10. To evaluate mechanisms involved in CVB3-induced pathogenesis of myocarditis, we determined the relationship of inducible nitric-oxide synthase (iNOS) mRNA expression with IFN-{gamma} and IL-10 secretion during CVB3 infection in different mouse strains. We found in susceptible A.BY/SnJ mice that develop ongoing myocarditis, a low and delayed IFN-{gamma} secretion and highly diminished IL-10 production compared with resistant C57BL/6 mice. Consequently, iNOS mRNA synthesis was delayed but clearly prolonged in susceptible mice. IL-10 gene-deficient mice confirmed the regulatory role of IL-10 in the outcome of CVB3 myocarditis. These mice did not establish a persistent cardiac infection and revealed IFN-{gamma} secretion kinetics similar to resistant mice but showed a slightly elongated cardiac iNOS mRNA expression resulting in extended myocarditis. We conclude that coordinated secretion of IFN-{gamma} and IL-10 is crucial for the effective resolution of CVB3 myocarditis. Moreover, lack of regulatory IL-10 leads to uncontrolled iNOS mRNA production, thus contributing to ongoing myocardial injury.




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