MODIFICATION OF VIRAL MYOCARDITIS IN MICE BY INTERLEUKIN-6

Inflammatory cytokines play a key role in the myocardial injury produc ed by viral myocarditis. Although interleukin-6 (IL-6) reportedly poss esses antiviral properties, its effect in viral myocarditis is unclear . To investigate the role of IL-6 in viral myocarditis induced by ence phalomyocarditis virus (EMCV) in mice, we evaluated (1) the survival r ate following IL-6 administration, (2) the viral titer in the heart, ( 3) viral replication in the heart by in situ hybridization, (4) histop athological changes using immunohistochemical staining, (5) neutralizi ng antibody against EMCV, (6) circulating interferon and tumor necrosi s factor-alpha (TNF-alpha), (7) viral suppression in vitro by IL-6, an d (8) natural killer (NK)-cell activity. Eight-week-old C3H/HeJ mice w ere injected intraperitoneally with EMCV (day 0) and were also injecte d subcutaneously twice daily for 4 consecutive days with 10 mu g/0.1 m L of human IL-6 on day -4 (group A), day 0 (group B), or day +4 (group D) for 4 days. As a control, 0.1 mL PBS instead of IL-6 was injected on day 0 for 4 days (group C). Certain mice were killed on day 4. The myocardial virus titers, viral replication in situ, and NK-cell activi ty in the spleen were determined. Decreased viral liter and viral repl ication in the heart reduced the titer of circulating TNF-alpha, and l ower NK-cell activity was observed in group B versus group C (control group). The titer of neutralizing antibodies against EMCV was signific antly (P<.05) increased in group B compared with group C. The remainin g mice were killed on days 10 and 30 after infection. The ratio of hea rt weight (HW) to body weight (BW) and myocardial injury in group B we re reduced versus group C on days 10 and 30. The HW of group B on day 30 did not differ from the normal control group. The ratio of splenic weight to BW and the ratio of thymic weight to BW of group B increased on day 10, with expanded follicles observed in the spleen and enlarge ment of the medulla observed in the thymus. Immunohistochemical study revealed an increased percentage of macrophages in the heart and splee n of group B. In summary, IL-6 reduces myocardial damage in mice with viral myocarditis. Modification of immune responses together with redu ction in viral replication appears to be the mechanism of the IL-6 eff ect. Although IL-6 is likely important in the process of viral antigen presentation, early activation of immune responses and attenuation of viral replication appear most significant, as reflected in the limite d time window during which IL-6 is effective in myocarditis.