Effect of interleukin-18 on viral myocarditis: enhancement of interferon- gamma and natural killer cell activity.

Encephalomyocarditis virus causes viral myocarditis with myocyte necrosis and inflammatory cell infiltration in mice. Because previous studies have shown that some cytokines prevent the sequelae of myocarditis, we assessed the effect of a newly identified cytokine, interleukin-18 (IL-18), in preventing the sequelae of myocarditis. Murine IL-18 (10 microg/day/mouse) was given peritoneally for 10 days in C3H mice infected with EMC virus. Mice were divided into group IL-18 (infected-treated), saline group (infected-untreated), group IL-18-2 (treatment started on day 2), group IL-18-5 (treatment started on day 5). Although the 14-day survival rate in saline group was 20%, that in the group IL-18 increased to 80% (P<0.05). Either mice in group IL-18-2 or in group IL-18-5 did not survive longer than saline group. The viral titer of the heart on day 3 was lower in group IL-18 compared to the saline group (1.00+/-0.20 log(10)tissue culture infected dose (TCID)(50)/mg wet weight v 1.42+/-0.12 log(10)TCID(50)/mg, n=3 of each). Mice in group IL-18 had less myocardial necrosis and cellular infiltration than the saline group. The myocardial expression of interferon- gamma (IFN- gamma) mRNA in group IL-18 was significantly (P<0.05) greater than the saline group on days 1 and 3 after viral inoculation. Circulating IFN- gamma was significantly elevated on days 1, 5, and 7, but significantly reduced on day 3. The natural killer cell activities in the spleen on days 1, 3, and 5 were significantly (P<0.05) greater in group IL-18 than in the saline group (41+/-9%v 10+/-6% on day 3, 4 of each). We conclude that IL-18 reduces the severity of EMC viral myocarditis by inducing cardiac expression of IFN- gamma mRNA and increasing splenic natural killer cell activity. Copyright 2000 Academic Press.