Department of Pharmacology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
Department of Pharmacology, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan.
J Neuroimmunol. 2021 Dec 15;361:577724. doi: 10.1016/j.jneuroim.2021.577724. Epub 2021 Sep 23.
Prostaglandin E (PGE) plays pivotal roles in controlling microglial activation with the EP receptor, a PGE receptor subtype. Activated microglia are often reported to increase cyclooxygenase (COX)-2 expression, followed by PGE production, but it is unclear whether extracellular PGE is involved in microglial PGE synthesis. In the present study, we report that PGE increases COX-2 protein in microglia. In a culture system, PGE at 10 M for 3 h increased COX-2 and microsomal PGE synthase (mPGES)-1 mRNA levels, and reduced mPGES-2, but did not affect COX-1 or cytosolic PGE synthase (cPGES) in microglia. PGE at 10 M for 3 h also increased the COX-2 protein level, but did not affect COX-1, mPGES-1, mPGES-2, or cPGES. An EP agonist, ONO-AE1-259-01, also increased COX-2 and mPGES-1 mRNA levels, and reduced mPGES-2, but did not affect COX-1 or cPGES, whereas an EP agonist, ONO-DI-004, an EP agonist, ONO-AE-248, and an EP agonist, ONO-AE1-329, had no effect. Similar to PGE, ONO-AE1-259-01 increased the COX-2 protein level, but did not affect COX-1, mPGES-1, mPGES-2, or cPGES. In addition, the effects of PGE were inhibited by an EP antagonist, PF-04418948, but not by an EP antagonist, ONO-8713, an EP antagonist, ONO-AE3-240, or an EP antagonist, ONO-AE3-208, at 10 M. On the other hand, lipopolysaccharide (LPS) increased PGE production, but the LPS-induced PGE production was not affected by ONO-8713, PF-04418948, ONO-AE3-240, or ONO-AE3-208. These results indicate that PGE increases COX-2 protein in microglia through the EP receptor supporting the idea that extracellular PGE has a triggering aspect for microglial activation.
前列腺素 E（PGE）通过 PGE 受体（一种 PGE 受体亚型）在控制小胶质细胞激活方面发挥关键作用。通常有报道称，激活的小胶质细胞会增加环氧化酶（COX）-2 的表达，随后产生 PGE，但尚不清楚细胞外 PGE 是否参与小胶质细胞 PGE 的合成。在本研究中，我们报告 PGE 可增加小胶质细胞中的 COX-2 蛋白。在培养体系中，PGE 在 10 μM 下作用 3 小时可增加 COX-2 和微粒体 PGE 合酶（mPGES）-1 mRNA 水平，并降低 mPGES-2，但不影响 COX-1 或胞质 PGE 合酶（cPGES）。PGE 在 10 μM 下作用 3 小时也可增加 COX-2 蛋白水平，但不影响 COX-1、mPGES-1、mPGES-2 或 cPGES。EP 激动剂 ONO-AE1-259-01 也增加 COX-2 和 mPGES-1 mRNA 水平，并降低 mPGES-2，但不影响 COX-1 或 cPGES，而 EP 激动剂 ONO-DI-004、EP 激动剂 ONO-AE-248 和 EP 激动剂 ONO-AE1-329 则没有影响。类似于 PGE，ONO-AE1-259-01 增加 COX-2 蛋白水平，但不影响 COX-1、mPGES-1、mPGES-2 或 cPGES。此外，PGE 的作用可被 EP 拮抗剂 PF-04418948 抑制，但不能被 EP 拮抗剂 ONO-8713、EP 拮抗剂 ONO-AE3-240 或 EP 拮抗剂 ONO-AE3-208 抑制，而这些拮抗剂的浓度均为 10 μM。另一方面，脂多糖（LPS）增加了 PGE 的产生，但 LPS 诱导的 PGE 产生不受 ONO-8713、PF-04418948、ONO-AE3-240 或 ONO-AE3-208 的影响。这些结果表明，PGE 通过 EP 受体增加小胶质细胞中的 COX-2 蛋白，支持细胞外 PGE 对小胶质细胞激活具有触发作用的观点。
