Interleukin-12 receptor/STAT4 signaling is required for the development of autoimmune myocarditis in mice by an interferon-γ-independent pathway

• Published in: Circulation (New York, N.Y.) N.Y.), 2001-12, Vol.104 (25), p.3145-3151
• Main Authors: AFANASYEVA, Marina, WANG, Yan, KAYA, Ziya, STAFFORD, Elizabeth A, DOHMEN, K. Malte, AKHA, Amir A, ROSE, Noel R
• Format: Article
• Language: English
• Subjects: Animals; Autoimmune Diseases - pathology; Autoimmune Diseases - physiopathology; Autoimmune Diseases - prevention & control; Biological and medical sciences; Cardiology. Vascular system; CD3 Complex - analysis; CD4 Antigens - analysis; CD8 Antigens - analysis; Cells, Cultured; Cytokines - drug effects; Cytokines - metabolism; DNA-Binding Proteins - genetics; DNA-Binding Proteins - physiology; Female; Flow Cytometry; Genotype; Heart; Interferon-gamma - genetics; Interferon-gamma - pharmacology; Interferon-gamma - physiology; Interleukin-12 - pharmacology; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Knockout; Myocarditis - pathology; Myocarditis - physiopathology; Myocarditis - prevention & control; Myocarditis. Cardiomyopathies; Myocardium - immunology; Myocardium - pathology; Myosins - immunology; Receptors, Interleukin - genetics; Receptors, Interleukin - physiology; Receptors, Interleukin-12; Signal Transduction; Spleen - cytology; Spleen - drug effects; Spleen - metabolism; STAT4 Transcription Factor; T-Lymphocytes - cytology; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Trans-Activators - genetics; Trans-Activators - physiology
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/hc5001.100629

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. 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.