Prostaglandin E2-EP4 signaling promotes immune inflammation through TH1 cell differentiation and TH17 cell expansion
Prostaglandin E2-EP4 signaling promotes immune inflammation through TH1 cell differentiation and TH17 cell expansion
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DOI：
10.1038/nm.1968
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发表时间：
2009-06-01
期刊：
影响因子：
82.9
通讯作者：
Narumiya, Shuh
中科院分区：
文献类型：
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作者：
Yao, Chengcan;Sakata, Daiji;Narumiya, Shuh
两种不同的辅助性T（T-H）亚群T（H）1和T（H）17在多种免疫疾病的动物模型中介导组织损伤和炎症，所述免疫疾病例如多发性硬化症、类风湿性关节炎、炎性肠病和过敏性皮肤病。这些实验结果，以及这些TH亚群在人类疾病中的意义，表明需要药理学措施来操纵这些TH亚群。我们发现，前列腺素E-2（PGE（2））作用于T细胞和树突状细胞上的受体EP 4，不仅促进T（H）1细胞分化，而且增强白细胞介素-23介导的T（H）17细胞体外扩增。在患有实验性自身免疫性脑脊髓炎或接触性超敏反应的小鼠中，体内给予EP 4选择性拮抗剂可减少T（H）1和T（H）17细胞在局部淋巴结中的积聚，并抑制疾病进展。因此，PGE（2）-EP 4信号传导通过T（H）1分化和T（H）17扩增促进免疫炎症，并且EP 4拮抗作用可能对各种免疫疾病有治疗作用。
Two distinct helper T (T-H) subsets, T(H)1 and T(H)17, mediate tissue damage and inflammation in animal models of various immune diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases and allergic skin disorders. These experimental findings, and the implication of these TH subsets in human diseases, suggest the need for pharmacological measures to manipulate these TH subsets. Here we show that prostaglandin E-2 (PGE(2)) acting on its receptor EP4 on T cells and dendritic cells not only facilitates T(H)1 cell differentiation but also amplifies interleukin-23-mediated T(H)17 cell expansion in vitro. Administration of an EP4-selective antagonist in vivo decreases accumulation of both T(H)1 and T(H)17 cells in regional lymph nodes and suppresses the disease progression in mice subjected to experimental autoimmune encephalomyelitis or contact hypersensitivity. Thus, PGE(2)-EP4 signaling promotes immune inflammation through T(H)1 differentiation and T(H)17 expansion, and EP4 antagonism may be therapeutically useful for various immune diseases.