ABSTRACT
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.
Subject(s)
Autoimmune Diseases/physiopathology , DNA-Binding Proteins/physiology , Interferon-gamma/physiology , Myocarditis/physiopathology , Receptors, Interleukin/physiology , Trans-Activators/physiology , Animals , Autoimmune Diseases/pathology , Autoimmune Diseases/prevention & control , CD3 Complex/analysis , CD4 Antigens/analysis , CD8 Antigens/analysis , Cells, Cultured , Cytokines/drug effects , Cytokines/metabolism , DNA-Binding Proteins/genetics , Female , Flow Cytometry , Genotype , Interferon-gamma/genetics , Interferon-gamma/pharmacology , Interleukin-12/pharmacology , Mice , Mice, Inbred BALB C , Mice, Knockout , Myocarditis/pathology , Myocarditis/prevention & control , Myocardium/immunology , Myocardium/pathology , Myosins/immunology , Receptors, Interleukin/genetics , Receptors, Interleukin-12 , STAT4 Transcription Factor , Signal Transduction , Spleen/cytology , Spleen/drug effects , Spleen/metabolism , T-Lymphocytes/cytology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology , Trans-Activators/geneticsABSTRACT
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.
