Abnormal T cell activation caused by the imbalance of the IL-1/IL-1R antagonist system is responsible for the development of experimental autoimmune encephalomyelitis
Abnormal T cell activation caused by the imbalance of the IL-1/IL-1R antagonist system is responsible for the development of experimental autoimmune encephalomyelitis
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DOI：
10.1093/intimm/dxh379
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发表时间：
2006-02-01
影响因子：
4.4
通讯作者：
Iwakura, Y
中科院分区：
文献类型：
--
作者：
Matsuki, T;Nakae, S;Iwakura, Y
IL-1是一种促炎细胞因子，在炎症和宿主对感染的反应中起重要作用。我们以前已经表明，IL-1和IL-1 R拮抗剂（IL-1 Ra）系统的失衡导致炎症性疾病的发展。为了探讨IL-1/IL-1 Ra系统在自身免疫性疾病中的作用，我们分析了髓鞘少突胶质细胞糖蛋白（MOG）诱导的实验性自身免疫性脑脊髓炎（EAE）小鼠携带靶向破坏IL-1 α，IL-1 β，IL-1 α和IL-1 β（IL-1）或IL-1 Ra基因。IL-1 α/β双缺陷（IL-1（-/-））小鼠表现出对EAE诱导的显著抗性，疾病严重程度显著降低，而IL-1 α（-/-）或IL-1 β（-/-）小鼠以与野生型小鼠相似的方式发生EAE。IL-1 Ra（-/-）小鼠在百日咳毒素（PTx）给药后也正常发生MOG诱导的EAE。然而，与野生型小鼠相反，这些小鼠在没有PTx给药的情况下对EAE诱导高度敏感。我们发现，在MOG刺激后，IL-1（-/-）T细胞中IFN-γ和IL-17的产生和增殖均减少，而IL-1 Ra（-/-）T细胞中IFN-γ、IL-17和肿瘤坏死因子-α的产生和增殖增强。这些观察结果表明，IL-1/IL-1 Ra系统是至关重要的自身抗原特异性T细胞诱导，并有助于EAE的发展。
IL-1 is a pro-inflammatory cytokine that plays an important role in inflammation and host responses to infection. We have previously shown that imbalances in the IL-1 and IL-1R antagonist (IL-1Ra) system cause the development of inflammatory diseases. To explore the role of the IL-1/IL-1Ra system in autoimmune disease, we analyzed myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in mice bearing targeted disruptions of the IL-1 alpha, IL-1 beta, IL-1 alpha and IL-1 beta (IL-1) or IL-1Ra genes. IL-1 alpha/beta double-deficient (IL-1(-/-)) mice exhibited significant resistance to EAE induction with a significant reduction in disease severity, while IL-1 alpha(-/-) or IL-1 beta(-/-) mice developed EAE in a manner similar to wild-type mice. IL-1Ra(-/-) mice also developed MOG-induced EAE normally with pertussis toxin (PTx) administration. In contrast to wild-type mice, however, these mice were highly susceptible to EAE induction in the absence of PTx administration. We found that both IFN-gamma and IL-17 production and proliferation were reduced in IL-1(-/-) T cells upon stimulation with MOG, while IFN-gamma, IL-17 and tumor necrosis factor-alpha production and proliferation were enhanced in IL-1Ra(-/-) T cells. These observations suggest that the IL-1/IL-1Ra system is crucial for auto-antigen-specific T cell induction and contributes to the development of EAE.