Tumor necrosis factor and viral myocarditis: the fine line between innate and inappropriate immune responses in the heart.

Abstract

“In this world there are only two tragedies. One is not getting what one wants, and the other is getting it.”—Oscar Wilde Tumor necrosis factor (TNF) has been referred to a “mixed blessing for higher organisms.”1 That is to say, although the controlled self-limited expression of TNF plays a critical role in activating host defense mechanisms and in homeostatic tissue repair, uncontrolled overexpression of TNF produces devastating consequences for the host organism, frequently leading to diffuse inflammation, multiorgan dysfunction, hemodynamic collapse, and death. Although a similar “bifunctional picture” for TNF has not yet emerged clearly for the heart, the report by Wada and colleagues2 in the present issue of Circulation suggests that TNF may be a mixed blessing for the heart as well. Several lines of evidence suggest that proinflammatory cytokines, such as TNF, play an important role in the pathogenesis of viral myocarditis. For example, elevated levels of TNF have been reported in patients with viral myocarditis.3 Importantly, TNF mRNA and protein are consistently upregulated in the hearts of patients with viral myocarditis.4 Mice with targeted overexpression of TNF in the cardiac compartment develop florid myocarditis and progressive myocardial fibrosis.5 6 The exogenous administration of TNF aggravates myocarditis, and the neutralization of TNF by antibodies or soluble receptors attenuates viral myocarditis.7 8 Taken together, these observations suggest that TNF plays an important pathophysiological role in the development and progression of viral myocarditis. In the present issue of Circulation , Wada and colleagues2 report that mice with targeted disruption of the TNF gene (TNF−/−) had increased mortality after infection with the encephalomyocarditis virus compared with wild-type mice (TNF+/+). Moreover, they showed that exogenous administration of TNF prevented the increase in virus–induced mortality in the TNF−/− mice. On the basis of …