Interferons in enteroviral heart disease: modulation of cytokine expression and antiviral activity

Interferon (IFN)-beta has a more than 120-fold higher antiviral activity than the closely related IFN-alpha in human myocardial fibroblasts infected with the cardiotropic enterovirus coxsackievirus B3 (CVB3). CVB3 replication induces interleukin (IL)-6 and IL-8 expression in myocardial fibroblasts, and suppresses the expression of monocyte chemoattractant protein-1 (MCP-1). We investigated whether the higher antiviral activity of IFN-beta compared to IFN-alpha was a result of a suppression of IL-8 expression by IFN-beta since previous studies had indicated that IL-8 stimulates enterovirus replication. Human myocardial fibroblasts were treated with either IFN-alpha, IFN-beta or IFN-gamma (0, 10, 100, or 1,000 IU/ml) and the concentrations of IL-6, IL-8 and MCP-1 were measured in culture supernatants by immunoassays. Both IFN-beta and IFN-gamma reduced IL-6 and IL-8 expression significantly. In addition, neutralization of IL-8 in culture supernatants of myocardial fibroblasts using a monoclonal antibody demonstrated a significant reduction of CVB3 titers. Antiproliferative effects of all three IFNs were very low (<30% with 1,000 IU/ml), indicating that the suppression IL-6 and IL-8 was not related to cytotoxicity. MCP-1 expression was increased only by high concentrations of IFN-gamma (1,000 IU/ml). By contrast, IFN-alpha had no significant effect on IL-6, IL-8 and MCP-1 expression. In conclusion, suppression of IL-8 expression is an "immuno-modulating" feature of IFN-beta in human myocardial fibroblasts, which is similar to the activity of IFN-gamma. This feature of IFN-beta contributes to its high antiviral activity against CVB3 and may be useful in the treatment of enteroviral heart disease.