Tumor Necrosis Factor-α (TNF-α) Plays a Protective Role in Acute Viral Myocarditis in Mice

Abstract

Background —It has been reported that tumor necrosis factor-α (TNF-α) is expressed in the heart with viral myocarditis and that its expression aggravates the condition. The pathophysiological effects of TNF-α on viral myocarditis, however, have not been fully elucidated. Methods and Results —To investigate the role of TNF-α in the progression of viral myocarditis, we used TNF-α gene–deficient mice (TNF-α −/− ) and induced acute myocarditis by infection with encephalomyocarditis virus (EMCV). The survival rate of TNF-α −/− mice after EMCV infection was significantly lower than that of TNF-α +/+ mice (0% versus 67% on day 14). Injection of recombinant human TNF-α (0.2 to 4.0 μg/mouse IV) improved the survival of TNF-α −/− mice in a dose-dependent manner, indicating that TNF-α is essential for protection against viral myocarditis. The levels of viral titer and viral genomic RNA of EMCV in the myocardium were significantly higher in TNF-α −/− than in TNF-α +/+ mice. Histopathological examination showed that the inflammatory changes of the myocardium were less marked in TNF-α −/− than in TNF-α +/+ mice. Immunohistochemical analysis revealed that the levels of immunoreactivity of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 in the myocardium were decreased in TNF-α −/− mice compared with TNF-α +/+ mice. Conclusions —These observations suggested that TNF-α is necessary for adhesion molecule expression and to recruit leukocytes to inflammatory sites, and thus, the lack of this cytokine resulted in failure of elimination of infectious agents. We concluded that TNF-α plays a protective role in the acute stage of viral myocarditis.

Overexpression of tumor necrosis factor (TNF)α and TNFα receptor I in human viral myocarditis: clinicopathologic correlations

“…TNFa enhances chemotaxis of macrophages and neutrophils, increases their phagocytic and cytotoxic activity 41 and promotes leukostasis by inducing increased expression of intracellular adhesion molecules and endothelial leukocyte adhesion molecules at sites of inflammation. Therefore, the presence of TNFa, as recently described by Wada et al, 42 plays a protective role in the early stage of encephalomyocarditis virus myocarditis, possibly through leukocyte recruitment, thus hindering viral replication. On the contrary at higher concentrations, TNFa production exceeds the number of its receptors located on the cell surface with an excess amount released into circulation.…”

l-Tryptophan–Kynurenine Pathway Metabolites Regulate Type I IFNs of Acute Viral Myocarditis in Mice

“…Sections (thickness, 4 mm) were used for H&E staining and IDO immunohistochemical staining as described in a previous report (16). Two pathologists who did not have any knowledge of the study design graded the extent of cellular infiltration and myocardial necrosis in tissue samples according to the following scale: 0, no lesions; 1+, lesions involving ,25%; 2+, lesions involving 25-50%; 3+, lesions involving 50-75%; and 4+, lesions involving 75-100% (20).…”

Tumor-Necrosis-Factor-.ALPHA.-Gene-Deficient Mice Have Improved Cardiac Function Through Reduction of Intercellular Adhesion Molecule-1 in Myocardial Infarction

“…In a viral myocarditis model of TNF-KO mice, reduced cellular infiltration and attenuated ICAM-1 immunoreactivity has been demonstrated as compared to WT mice. 30 …”