Antiviral and immunoregulatory activities of IFN-γ depend on constitutively expressed IL-1α

IFN-gamma induces its immunoregulatory activities by activating genes mainly through the Jak-STAT signaling pathway. Here we show that what was considered to be intrinsic IFN-gamma activities depend largely on the basal level of NF-kappa B, which is maintained by constitutively expressed IL-1 alpha. The IL-1 receptor antagonist and antibodies to IL-1 alpha, but not to IL-1 beta, inhibited the antiviral activity of IFN-gamma by 90%, whereas no inhibition of type I IFN activity was observed. Similarly, the induction of many genes by IFN-gamma, including HLA-DR, ICAM-1, IL-18BP, and genes mediating its antiviral activity, greatly depended on basal IL-1 alpha. Furthermore, IFN-gamma induced serum IL-18 binding protein in wild-type mice but not in IL-1 alpha/beta double-deficient mice. Thus, constitutively expressed IL-1a is critical for numerous IFN-gamma activities.