Ischemia/reperfusion-induced IFN-gamma up-regulation: Involvement of IL-12and IL-18

Tissue injury as a consequence of ischemia followed by reperfusion is chara cterized by earl! as well as late signs of inflammation. The latter, among others, involves IFN-gamma-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 foll owing ischemia, IFN-gamma and IL-12 mRNA. are subsequently up-regulated st day 6 following ischemia. Combined, but not separate, in vivo neutralizatio n of the IFN-gamma inducing cytokines IL-12 and IL-18 reduces IFN-gamma-dep endent MHC class I and II up-regulation to a similar extent as IFN-gamma ne utralization, suggesting the involvement of functional IL-12, IL-18, and IF N-gamma protein. These results reveal a novel relationship between tissue i njury of nonmicrobial origin and the induction of IL-IZ as well as IL-18, T he collaboration observed between endogenous IL-12 and IL-18 in the inducti on of IFN-gamma after renal ischemia/reperfusion, resembles the immune resp onse to bacterial infections.