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

研究了前列腺素e2 （PGE_2）受体EP1、EP2、EP3、EP4在人牙龈成纤维细胞（HGF）和牙周韧带（PDL）细胞中的作用。分别用IL-1β和IL-1α刺激HGF和PDL细胞，产生IL-6和PGE_2。吲哚美辛对内源性PGE_2的抑制作用增强了il -1诱导的IL-6的产生，但完全抑制了il -1诱导的PGE_2的产生。外源性PGE_2抑制il -1诱导的两种细胞IL-6的产生。选择性EP2/EP3/EP4激动剂11-deoxy-PGE_1和选择性EP2激动剂butaprost抑制il -1诱导的IL-6产生，但butaprost的抑制作用不如11-deoxy-PGE_1。ONO-AP-324是一种EP3激动剂，不影响il -1诱导的IL-6的产生。17-苯基ω-三甲基PGE_2增强了il -1诱导的HGF中IL-6的产生。逆转录-聚合酶链反应分析证实EP2和EP4 mRNA在PDL细胞中表达。二丁基cAMP （cAMP类似物）和腺苷酸环化酶激活剂forskolin（腺苷酸环化酶激活剂）可降低il -1刺激的细胞产生IL-6。由此可见，在HGF和PDL细胞中，PGE_2通过cAMP依赖通路，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疾病中起关键作用。

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.