Tissue injury as a consequence of ischemia followed by reperfusion is characterized by early as well as late signs of inflammation. The latter, among others, involves IFN-γ-dependent up-regulation of MHC class I and II Ag expression. Employing a murine model of renal ischemia, we show that renal IL-18 mRNA up-regulation coincides with caspase-1 activation at day 1 following ischemia. IFN-γ and IL-12 mRNA are subsequently up-regulated at day 6 following ischemia. Combined, but not separate, in vivo neutralization of the IFN-γ inducing cytokines IL-12 and IL-18 reduces IFN-γ-dependent MHC class I and II up-regulation to a similar extent as IFN-γ neutralization, suggesting the involvement of functional IL-12, IL-18, and IFN-γ protein. These results reveal a novel relationship between tissue injury of nonmicrobial origin and the induction of IL-12 as well as IL-18. The collaboration observed between endogenous IL-12 and IL-18 in the induction of IFN-γ after renal ischemia/reperfusion, resembles the immune response to bacterial infections.