STAT3 and NF-κB signal pathway is required for IL-23-mediated IL-17 production in spontaneous arthritis animal model IL-1 receptor antagonist-deficient mice
STAT3 and NF-κB signal pathway is required for IL-23-mediated IL-17 production in spontaneous arthritis animal model IL-1 receptor antagonist-deficient mice
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DOI：
10.4049/jimmunol.176.9.5652
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发表时间：
2006-05-01
影响因子：
4.4
通讯作者：
Kim, Ho-Youn
中科院分区：
文献类型：
--
作者：
Cho, Mi-La;Kang, Jung-Won;Kim, Ho-Youn
IL-23是由IL-12的p19亚基和p40亚基组成的异二聚体细胞因子。IL-23具有促炎活性，诱导活化的CD 4（+）T细胞分泌IL-17并刺激记忆性CD 4（+）T细胞的增殖。我们研究了缺乏IL-1 R拮抗剂（1 L-1 Ra（-/-））的小鼠（自发性关节炎的动物模型）中CD 4（+）T细胞中IL-23的致病作用。IL-23在IL-1 Ra（-/-）小鼠的炎症关节中强烈表达。表达小鼠IL-23的重组腺病毒（rAd/mIL-23）显著加速了这种关节炎症和关节破坏。IL-1 β进一步增加IL-23的产生，从而诱导IL-1 Ra（-/-）小鼠脾CD 4（+）T细胞中IL-17的产生和OX 40的表达。用抗p19抗体阻断IL-23可阻断IL-1诱导的脾细胞产生IL-17。IL-23诱导CD 4（+）T细胞产生IL-17的过程通过激活Jak 2、PI 3 K/Akt、STAT 3和NF-κ B B介导，而p38 MAPK和AP-1不参与该过程。我们的数据表明IL-23是IL-1和IL-17之间的联系。IL-23似乎是自发性关节炎IL-1 Ra（-/-）模型发病机制中的一种中心促炎细胞因子。其细胞内信号通路可能成为治疗自身免疫性关节炎的有用治疗靶点。
IL-23 is a heterodimeric cytokine composed of a p19 subunit and the p40 subunit of IL-12. IL-23 has proinflammatory activity, inducing IL-17 secretion from activated CD4(+) T cells and stimulating the proliferation of memory CD4(+) T cells. We investigated the pathogenic role of IL-23 in CD4(+) T cells in mice lacking the IL-1R antagonist (1L-1Ra(-/-)), an animal model of spontaneous arthritis. IL-23 was strongly expressed in the inflamed joints of IL-1Ra(-/-) mice. Recombinant adenovirus expressing mouse IL-23 (rAd/mIL-23) significantly accelerated this joint inflammation and joint destruction. IL-1 beta further increased the production of IL-23, which induced IL-17 production and OX40 expression in splenic CD4(+) T cells of IL-1Ra(-/-) mice. Blocking IL-23 with anti-p19 Ab abolished the IL-17 production induced by IL-1 in splenocyte cultures. The process of IL-23-induced IL-17 production in CD4(+) T cells was mediated via the activation of Jak2, PI3K/Akt, STAT3, and NF-kappa B, whereas p38 MAPK and AP-1 did not participate in the process. Our data suggest that IL-23 is a link between IL-1 and IL-17. IL-23 seems to be a central proinflammatory cytokine in the pathogenesis of this IL-1Ra(-/-) model of spontaneous arthritis. Its intracellular signaling pathway could be useful therapeutic targets in the treatment of autoimmune arthritis.