Interleukin-12 Receptor/STAT4 Signaling Is Required for the Development of Autoimmune Myocarditis in Mice by an Interferon- –Independent Pathway

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). 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-12R 1–deficient mice and STAT4-deficient mice were resistant to the induction of myocarditis. Treatment with exogenous IL-12 exacerbated disease. We questioned whether IFNis required for the disease-promoting activity of IL-12. On the contrary, we found that IFNsuppresses EAM. Lack of IFNdue to either depletion with an antibody or a genetic deficiency exacerbated myocarditis. Spleens from IFN–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 IFNsuppressed the development of myocarditis. Conclusions—IL-12/IL-12R/STAT4 signaling promotes the development of EAM. In contrast, IFNplays a protective role. The disease-limiting effects of IFNmight be explained by its ability to control the expansion of activated T lymphocytes. (Circulation. 2001;104:3145-3151.)