Department of Obstetrics and Gynecology, The University of Tokyo, Tokyo 113-8655, Japan.
Extra Value Generation Drug Discovery Unit, Takeda Pharmaceutical Company, Fujisawa, Kanagawa 251-8555, Japan.
Mol Hum Reprod. 2021 Jan 22;27(1). doi: 10.1093/molehr/gaaa077.
Non-hormonal therapeutic strategies for endometriosis are needed. The aim of this study was to characterize the effects of prostaglandin (PG)E2 receptor inhibitors to explore their potential as novel therapeutic strategies for endometriosis. The expression of PGE2 receptors (EP2 and EP4) in donated tissues from human ovarian endometriosis, adenomyosis and peritoneal endometriosis was examined using immunohistochemistry. Human endometriotic stromal cells (ESC) isolated from ovarian endometriotic tissue and peritoneal macrophages were treated with EP2 and EP4 antagonists. cAMP accumulation and the effect of EP antagonists were measured using cAMP assays. DNA synthesis in ESC was detected using bromodeoxyuridine incorporation analysis. Interleukin (IL)-6 and IL-8 protein levels in ESC supernatants were measured using ELISAs. mRNA expression level for aromatase by ESC, and selected cytokines by peritoneal macrophages was measured using RT-PCR. EP2 and EP4 receptors were expressed in cells derived from control and diseased tissue, ovarian endometriotic, adenomyotic and peritoneal lesions. A selective EP2 antagonist reduced DNA synthesis, cAMP accumulation and IL-1β-induced proinflammatory cytokine secretion and aromatase expression. A selective EP4 antagonist negated IL-1β-induced IL-6 secretion and aromatase expression. In peritoneal macrophages, EP expression was elevated in endometriosis samples but the EP4 antagonist reduced cAMP levels and expression of vascular endothelial growth factor, chemokine ligand 2 and chemokine ligand 3 mRNA. EP2 and EP4 are functioning in endometriosis lesions and peritoneal macrophages, and their selective antagonists can reduce EP-mediated actions, therefore, the EP antagonists are potential therapeutic agents for controlling endometriosis.
需要寻找非激素治疗子宫内膜异位症的方法。本研究旨在研究前列腺素（PG）E2 受体抑制剂的作用，以探索其作为子宫内膜异位症新型治疗策略的潜力。通过免疫组织化学法检测人卵巢子宫内膜异位症、子宫腺肌病和腹膜子宫内膜异位症组织中 PGE2 受体（EP2 和 EP4）的表达。用人卵巢子宫内膜异位症组织中分离的子宫内膜间质细胞（ESC）和腹膜巨噬细胞处理 EP2 和 EP4 拮抗剂。使用 cAMP 测定法测定 cAMP 积累和 EP 拮抗剂的作用。通过溴脱氧尿苷掺入分析检测 ESC 中的 DNA 合成。使用 ELISA 检测 ESC 上清液中白细胞介素（IL）-6 和 IL-8 蛋白水平。通过 RT-PCR 检测 ESC 中芳香酶和腹膜巨噬细胞中选定细胞因子的 mRNA 表达水平。EP2 和 EP4 受体在来自对照和患病组织、卵巢子宫内膜异位症、子宫腺肌病和腹膜病变的细胞中表达。选择性 EP2 拮抗剂可减少 DNA 合成、cAMP 积累和 IL-1β诱导的促炎细胞因子分泌和芳香酶表达。选择性 EP4 拮抗剂可消除 IL-1β诱导的 IL-6 分泌和芳香酶表达。在腹膜巨噬细胞中，子宫内膜异位症样本中 EP 表达增加，但 EP4 拮抗剂可降低 cAMP 水平和血管内皮生长因子、趋化因子配体 2 和趋化因子配体 3 mRNA 的表达。EP2 和 EP4 在子宫内膜异位症病变和腹膜巨噬细胞中起作用，其选择性拮抗剂可减少 EP 介导的作用，因此，EP 拮抗剂是控制子宫内膜异位症的潜在治疗药物。
