IL-12/IL-12R/STAT4 signaling promotes the development of experimental autoimmune myocarditis in mice, whereas IFN-gamma plays a protective role by suppressing the disease.
In a murine model of autoimmune myocarditis, IL-12/STAT4 signaling promotes disease development while IFN-gamma unexpectedly plays a protective role by controlling the expansion of activated T lymphocytes.
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)-gamma. 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-12Rbeta1-deficient mice and STAT4-deficient mice were resistant to the induction of myocarditis. Treatment with exogenous IL-12 exacerbated disease. We questioned whether IFN-gamma is required for the disease-promoting activity of IL-12. On the contrary, we found that IFN-gamma suppresses EAM. Lack of IFN-gamma due to either depletion with an antibody or a genetic deficiency exacerbated myocarditis. Spleens from IFN-gamma-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-gamma suppressed the development of myocarditis. CONCLUSIONS: IL-12/IL-12R/STAT4 signaling promotes the development of EAM. In contrast, IFN-gamma plays a protective role. The disease-limiting effects of IFN-gamma might be explained by its ability to control the expansion of activated T lymphocytes.
Afanasyeva et al. (Mon,) conducted a other in Experimental autoimmune myocarditis. IL-12Rbeta1 deficiency, STAT4 deficiency, exogenous IL-12, and IFN-gamma modulation vs. Wild-type or untreated control mice was evaluated on Development of autoimmune myocarditis. IL-12/IL-12R/STAT4 signaling promotes the development of experimental autoimmune myocarditis in mice, whereas IFN-gamma plays a protective role by suppressing the disease.