Background— Interleukin (IL)-12 exerts a potent proinflammatory effect by stimulating T-helper (Th) 1 responses. This effect is believed to be mediated primarily through the activation of STAT4 and subsequent production of interferon (IFN)-γ.

Methods and Results— We examined the role of IL-12 receptor (IL-12R) signaling in the development of murine experimental autoimmune myocarditis (EAM) induced by cardiac myosin immunization. Both IL-12Rβ1–deficient mice and STAT4-deficient mice were resistant to the induction of myocarditis. Treatment with exogenous IL-12 exacerbated disease. We questioned whether IFN-γ is required for the disease-promoting activity of IL-12. On the contrary, we found that IFN-γ suppresses EAM. Lack of IFN-γ due to either depletion with an antibody or a genetic deficiency exacerbated myocarditis. Spleens from IFN-γ–deficient mice immunized with cardiac myosin showed increased cellularity; greater numbers of CD3+, CD4+, CD8+, and IL-2–producing cells; and heightened ability to produce cytokines on stimulation in vitro. Treatment of mice with recombinant IFN-γ suppressed the development of myocarditis.

Conclusions— IL-12/IL-12R/STAT4 signaling promotes the development of EAM. In contrast, IFN-γ plays a protective role. The disease-limiting effects of IFN-γ might be explained by its ability to control the expansion of activated T lymphocytes.