Cyclooxygenase-2 Inhibits T Helper Cell Type 9 Differentiation during Allergic Lung Inflammation via Down-regulation of IL-17RB
Cyclooxygenase-2 Inhibits T Helper Cell Type 9 Differentiation during Allergic Lung Inflammation via Down-regulation of IL-17RB
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DOI：
10.1164/rccm.201211-2073oc
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发表时间：
2013-04-15
影响因子：
24.7
通讯作者：
Zeldin, Darryl C.
中科院分区：
文献类型：
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作者：
Li, Hong;Edin, Matthew L.;Zeldin, Darryl C.
基本原理：辅助 CD4(+) T 细胞亚群，包括产生 IL-9 和 IL-10 的 9 型辅助 T 细胞 (Th9) 细胞，存在于某些炎症条件下。环加氧酶 (COX)-1 和 COX-2 在过敏性肺部炎症和哮喘中发挥重要作用。 COX 衍生的类二十烷酸是否在过敏性肺部炎症期间调节 Th9 细胞尚不清楚。目的：确定 COX 代谢物在过敏性肺部炎症期间调节 Th9 细胞分化和功能的作用。方法：使用流式细胞术、细胞因子测定、共聚焦显微镜、实时 PCR 和免疫印迹，在卵清蛋白诱导的过敏性炎症体内模型和 Th9 分化体外模型中对 COX-1(-/-)、COX-2(-/-) 和野生型 (WT) 小鼠进行研究。此外，还使用合成前列腺素 (PG)、选择性抑制剂和 siRNA 敲除来检查特定类二十烷酸及其受体的作用。测量和主要结果：COX-1(-/-) 和 WT 小鼠之间的实验终点没有差异；然而，与WT相比，过敏性COX-2(-/-)小鼠的肺、支气管肺泡灌洗液、淋巴结和血液中IL-9(+) CD4(+) T细胞的百分比增加。在过敏性COX-2(-/-)小鼠或用COX-2抑制剂治疗的WT小鼠中，支气管肺泡灌洗液IL-9和IL-10、血清IL-9和肺IL-17RB水平显着增加。 PGD(2) 和PGE(2) 抑制体内IL-9、IL-10 和IL-17RB 的表达，这也降低了体外小鼠和人初始CD4(+) T 细胞的Th9 细胞分化。抑制蛋白激酶A可显着增加体外从WT小鼠中分离的幼稚CD4(+) T细胞的Th9细胞分化。结论：COX-2 衍生的 PGD(2) 和 PGE(2) 通过蛋白激酶 A 依赖性机制抑制 IL-17RB 表达来调节 Th9 细胞分化。
Rationale: Helper CD4(+) T cell subsets, including IL-9-and IL-10-producing T helper cell type 9 (Th9) cells, exist under certain inflammatory conditions. Cyclooxygenase (COX)-1 and COX-2 play important roles in allergic lung inflammation and asthma. It is unknown whether COX-derived eicosanoids regulate Th9 cells during allergic lung inflammation.Objectives: To determine the role of COX metabolites in regulating Th9 cell differentiation and function during allergic lung inflammation. Methods: COX-1(-/-), COX-2(-/-), and wild-type (WT) mice were studied in an in vivo model of ovalbumin-induced allergic inflammation and an in vitro model of Th9 differentiation using flow cytometry, cytokine assays, confocal microscopy, real-time PCR, and immunoblotting. In addition, the role of specific eicosanoids and their receptors was examined using synthetic prostaglandins (PGs), selective inhibitors, and siRNA knockdown.Measurements and Main Results: Experimental endpoints were not different between COX-1(-/-) and WT mice; however, the percentage of IL-9(+) CD4(+) T cells was increased in lung, bronchoalveolar layage fluid, lymph nodes, and blood of allergic COX-2(-/-) mice relative to WT. Bronchoalyeolar lavage fluid IL-9 and IL-10, serum IL-9, and lung IL-17RB levels were significantly increased in allergic COX-2(-/-) mice or in WT mice treated with COX-2 inhibitors. IL-9, IL-10, and IL-17RB expression in vivo was inhibited by PGD(2) and PGE(2), which also reduced Th9 cell differentiation of murine and human naive CD4(+) T cells in vitro. Inhibition of protein kinase A significantly increased Th9 cell differentiation of naive CD4(+) T cells isolated from WT mice in vitro. Conclusions: COX-2-derived PGD(2) and PGE(2) regulate Th9 cell differentiation by suppressing IL-17RB expression via a protein kinase A-dependent mechanism.