RESUMEN
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.
Asunto(s)
Enfermedades Autoinmunes/fisiopatología , Proteínas de Unión al ADN/fisiología , Interferón gamma/fisiología , Miocarditis/fisiopatología , Receptores de Interleucina/fisiología , Transactivadores/fisiología , Animales , Enfermedades Autoinmunes/patología , Enfermedades Autoinmunes/prevención & control , Complejo CD3/análisis , Antígenos CD4/análisis , Antígenos CD8/análisis , Células Cultivadas , Citocinas/efectos de los fármacos , Citocinas/metabolismo , Proteínas de Unión al ADN/genética , Femenino , Citometría de Flujo , Genotipo , Interferón gamma/genética , Interferón gamma/farmacología , Interleucina-12/farmacología , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Miocarditis/patología , Miocarditis/prevención & control , Miocardio/inmunología , Miocardio/patología , Miosinas/inmunología , Receptores de Interleucina/genética , Receptores de Interleucina-12 , Factor de Transcripción STAT4 , Transducción de Señal , Bazo/citología , Bazo/efectos de los fármacos , Bazo/metabolismo , Linfocitos T/citología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Transactivadores/genéticaRESUMEN
Myocarditis is a principal cause of heart disease among young adults and is often a precursor of heart failure due to dilated cardiomyopathy. We show here that complement is critical for the induction of experimental autoimmune myocarditis and that it acts through complement receptor type 1 (CR1) and type 2 (CR2). We also found a subset of CD44(hi)CD62L(lo) T cells that expresses CR1 and CR2 and propose that both receptors are involved in the expression of B and T cell activation markers, T cell proliferation and cytokine production. These findings provide a mechanism by which activated complement, a key product of the innate immune response, modulates the induction of an autoimmune disease.