Caspase-1-Processed Cytokines IL-1β and IL-18 Promote IL-17 Production by γδ and CD4 T Cells That Mediate Autoimmunity
Caspase-1-Processed Cytokines IL-1β and IL-18 Promote IL-17 Production by γδ and CD4 T Cells That Mediate Autoimmunity
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DOI：
10.4049/jimmunol.1003597
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发表时间：
2011-05-15
影响因子：
4.4
通讯作者：
Mills, Kingston H. G.
中科院分区：
文献类型：
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作者：
Lalor, Stephen J.;Dungan, Lara S.;Mills, Kingston H. G.
IL-1β在促进GMAT和CD4T细胞产生IL-17中起关键作用。然而，IL-1靶向药物虽然对自体炎症性疾病有效，但对自体免疫性疾病效果较差。相反，NLRP3炎症体复合体中的功能获得突变与IL-1β和IL-18的产生以及Th17反应的增强有关。在这项研究中，我们研究了caspase-1加工的细胞因子在IL-17产生和实验性自身免疫性脑脊髓炎(EAE)诱导中的作用。杀死结核分枝杆菌，CFA中用于诱导EAE的免疫刺激成分，通过激活炎症体复合体和caspase-1刺激树突状细胞产生IL-1β和IL-18。用结核分枝杆菌和髓鞘少突胶质细胞糖蛋白刺激的树突状细胞促进T细胞产生IL-17，并在转移到幼鼠后诱导EAE，这种作用可被caspase-1抑制剂抑制，并被IL-1β或IL-18逆转。直接注射caspase-1抑制剂可抑制体内CD4T细胞和Gamma Delta T细胞产生IL-17，并减轻EAE的临床症状。与IL-1β和IL-23一样，γ-Delta T细胞表达高水平的IL-18R以及IL-18和IL-23的组合，在没有TCR参与的情况下，刺激Gamma Delta T细胞和CD4T细胞产生IL-17。我们的研究结果表明，caspase-1处理的细胞因子IL-1β和IL-18不仅通过刺激T细胞天然产生IL-17来促进自身免疫，而且还揭示了IL-1β和IL-18功能的冗余，提示caspase-1或炎症体可能是治疗自身免疫性疾病的重要药物靶点。免疫学杂志，2011,186：5738-5748。
IL-1 beta plays a critical role in promoting IL-17 production by gamma delta and CD4 T cells. However, IL-1-targeted drugs, although effective against autoinflammatory diseases, are less effective against autoimmune diseases. Conversely, gain-of-function mutations in the NLRP3 inflammasome complex are associated with enhanced IL-1 beta and IL-18 production and Th17 responses. In this study, we examined the role of caspase-1-processed cytokines in IL-17 production and in induction of experimental autoimmune encephalomyelitis (EAE). Killed Mycobacterium tuberculosis, the immunostimulatory component in CFA used for inducing EAE, stimulated IL-1 beta and IL-18 production by dendritic cells through activation of the inflammasome complex and caspase-1. Dendritic cells stimulated with M. tuberculosis and myelin oligodendrocyte glycoprotein promoted IL-17 production by T cells and induced EAE following transfer to naive mice, and this was suppressed by a caspase-1 inhibitor and reversed by administration of IL-1 beta or IL-18. Direct injection of the caspase-1 inhibitor suppressed IL-17 production by CD4 T cells and gamma delta T cells in vivo and attenuated the clinical signs of EAE. gamma delta T cells expressed high levels of IL-18R and the combination of IL-18 and IL-23, as with IL-1 beta and IL-23, stimulated IL-17 production by gamma delta T cells, but also from CD4 T cells, in the absence of TCR engagement. Our findings demonstrate that caspase-1-processed cytokines IL-1 beta and IL-18 not only promote autoimmunity by stimulating innate IL-17 production by T cells but also reveal redundancy in the functions of IL-1 beta and IL-18, suggesting that caspase-1 or the inflammasome may be an important drug target for autoimmune diseases. The Journal of Immunology, 2011, 186: 5738-5748.