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

被引:124
作者
Afanasyeva, M
Wang, Y
Kaya, Z
Stafford, EA
Dohmen, KM
Akha, AAS
Rose, NR
机构
[1] Johns Hopkins Med Inst, Dept Pathol, Baltimore, MD 21205 USA
[2] Johns Hopkins Med Inst, W Harry Feinstone Dept Mol Microbiol & Immunol, Baltimore, MD 21205 USA
关键词
immunology; interleukins; myocarditis; myosin; inflammation;
D O I
10.1161/hc5001.100629
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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-12R beta1 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.
引用
收藏
页码:3145 / 3151
页数:7
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