Study of roles of EP receptors and their clinical application in periodontal disease

我们研究了前列腺素 E_2 (PGE_2) 受体（分为 EP1、EP2、EP3、EP4）在人牙龈成纤维细胞 (HGF) 和牙周膜 (PDL) 细胞中的作用。 HGF和PDL细胞分别用IL-1β和IL-1α刺激，产生IL-6和PGE_2。环加氧酶抑制剂吲哚美辛对内源性 PGE_2 的抑制增强了 IL-1 诱导的 IL-6 的产生，尽管它完全抑制了 IL-1 诱导的 PGE_2 的产生。外源性 PGE_2 抑制两种类型细胞中 IL-1 诱导的 IL-6 产生。 11-脱氧-PGE_1（一种选择性 EP2/EP3/EP4 激动剂）和布他前列素（一种选择性 EP2 激动剂）可抑制 IL-1 诱导的 IL-6 产生，但布他前列素的效力不如 11-脱氧-PGE_1。 ONO-AP-324 是一种 EP3 激动剂，不能影响 IL-1 诱导的 IL-6 产生。 17-苯基-ω-三聚体 PGE_2 增强 HGF 中 IL-1 诱导的 IL-6 产生。逆转录聚合酶链反应分析证明 PDL 细胞中 EP2 和 EP4 的 mRNA 表达。二丁酰 cAMP（一种 cAMP 类似物）和毛喉素（一种腺苷酸环化酶激活剂）可减少 IL-1 刺激的细胞产生的 IL-6 总之，我们认为 PGE_2 通过 HGF 和 PDL 细胞中 cAMP 依赖性途径通过 EP2/EP4 受体下调 IL-1 诱导的 IL-6 产生。 EP2和/或EP4受体可能在控制炎症性牙周病中发挥关键作用。

We investigated the roles of prostaglandin E_2 (PGE_2) receptors, which are divided into EP1, EP2, EP3, EP4, in human gingival fibroblasts (HGF) and periodontal ligament (PDL) cells. HGF and PDL cells were stimulated with IL-1β and IL-1α, respectively, and produced IL-6 and PGE_2. Inhibition of endogenous PGE_2 by indomthacin, a cyclooxygenase inhibitor, enhanced IL-1-induced IL-6 production, although it completely inhibited IL-1-induced PGE_2 production. Exogenous PGE_2 suppressed IL-1-induced IL-6 production in both types of cells. 11-deoxy-PGE_1, a selective EP2/EP3/EP4 agonist, and butaprost, a selective EP2 agonist, inhibited IL-1-induced IL-6 production, although butaprost was less potent than 11-deoxy-PGE_1. ONO-AP-324, an EP3 agonist, could not affect IL-1-induced IL-6 production. 17-phenyl-ω-trinor PGE_2 enhanced IL-1-induced IL-6 production in HGF. Reverse transcription-polymerase chain reaction analysis demonstrated mRNA expression of EP2 and EP4 in PDL cells. Dibutyryl cAMP, a cAMP analog, and forskolin, an activator of adenylate cyclases, reduced IL-6 production by IL-1-stimulated cellsIn conclusion, we suggest that PGE_2 downregulates IL-1-induced IL-6production via EP2/EP4 receptors by cAMP-dependent pathways in both HGF and PDL cells. EP2 and/or EP4 receptors may play critical roles in controlling inflammatory periodontal conditions.