Dual role of the IL-12/IFN-gamma axis in the development of autoimmune myocarditis: Induction by IL-12 and protection by IFN-gamma

IL-12 and IFN-gamma positively regulate each other and type I inflammatory responses, which are believed to cause tissue damage in autoimmune diseases . We investigated the role of the IL-12/IFN-gamma (Th1) axis in the develop ment of autoimmune myocarditis. IL-12p40-deficient mice on a susceptible ba ckground resisted myocarditis. In the absence of IL-12, autospecific CD4(+) T cells proliferated poorly and showed increased Th2 cytokine responses. H owever, IFN-gamma -deficient mice developed fatal autoimmune disease, and b lockade of IL-4R signaling did not confer susceptibility to myocarditis in IL-12p40-deficient mice, demonstrating that IL-12 triggers autoimmunity by a mechanism independent of the effector cytokines IFN-gamma and IL-4. In co nclusion, our results, suggest that the IL-12/IFN-gamma axis is a double-ed ged sword for the development of autoimmune myocarditis. Although IL-12 med iates disease by induction/expansion of Th1-type cells, IFN-gamma productio n from these cells limits disease progression.