Cyclooxygenase-2 contributes to oxidopamine-mediated neuronal inflammation and injury via the prostaglandin E2 receptor EP2 subtype.
Cyclooxygenase-2 contributes to oxidopamine-mediated neuronal inflammation and injury via the prostaglandin E2 receptor EP2 subtype.
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环氧酶-2通过前列腺素E2受体EP2亚型有助于氧化氧化胺介导的神经元炎症和损伤。
DOI：
10.1038/s41598-017-09528-z
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发表时间：
2017-08-25
影响因子：
4.6
通讯作者：
Jiang J
中科院分区：
文献类型：
--
作者：
Kang X;Qiu J;Li Q;Bell KA;Du Y;Jung DW;Lee JY;Hao J;Jiang J
环氧合酶-2（考克斯-2）主要通过产生前列腺素E2（PGE 2）激活四种膜受体EP 1-EP 4来触发促炎过程，所述促炎过程可加重许多神经病症中的神经元变性和功能损伤。然而，哪种EP受体是考克斯-2/PGE 2介导的神经元炎症和变性的罪魁祸首仍然很不清楚，可能取决于损伤类型和反应成分。在此，我们证明了在两种神经元细胞系-小鼠Neuro-2a和人SH-SY 5 Y-中，在用神经毒素6-羟基多巴胺（6-OHDA）处理后，考克斯-2被诱导并显示核转位，导致PGE 2的生物合成和促炎细胞因子白细胞介素-1 β的上调。抑制考克斯-2或微粒体前列腺素E合酶-1抑制6-羟基多巴胺触发的PGE 2在这些细胞中的生产。用PGE 2或EP 2选择性激动剂布他前列素处理，而不是EP 4激动剂CAY 10598，增加了两种细胞系中的cAMP反应。我们最近开发的新型选择性EP 2拮抗剂TG 4 -155和TG 6 -10-1可阻断PGE 2诱导的cAMP产生，但EP 4选择性拮抗剂GW 627368 X不能阻断。TG 4 -155、TG 6 -10-1或考克斯-2选择性抑制剂塞来昔布可显著阻断6-OHDA诱导的细胞毒性，但GW 627368 X对6-OHDA诱导的细胞毒性无影响。我们的研究结果表明，前列腺素E2受体EP 2是考克斯-2活性启动的cAMP信号在6-OHDA处理后的Neuro-2a和SH-SY 5 Y细胞的关键介质，并有助于oxidopamine介导的神经毒性。
Cyclooxygenase-2 (COX-2) triggers pro-inflammatory processes that can aggravate neuronal degeneration and functional impairments in many neurological conditions, mainly via producing prostaglandin E2 (PGE2) that activates four membrane receptors, EP1-EP4. However, which EP receptor is the culprit of COX-2/PGE2-mediated neuronal inflammation and degeneration remains largely unclear and presumably depends on the insult types and responding components. Herein, we demonstrated that COX-2 was induced and showed nuclear translocation in two neuronal cell lines – mouse Neuro-2a and human SH-SY5Y – after treatment with neurotoxin 6-hydroxydopamine (6-OHDA), leading to the biosynthesis of PGE2 and upregulation of pro-inflammatory cytokine interleukin-1β. Inhibiting COX-2 or microsomal prostaglandin E synthase-1 suppressed the 6-OHDA-triggered PGE2 production in these cells. Treatment with PGE2 or EP2 selective agonist butaprost, but not EP4 agonist CAY10598, increased cAMP response in both cell lines. PGE2-initiated cAMP production in these cells was blocked by our recently developed novel selective EP2 antagonists – TG4-155 and TG6-10-1, but not by EP4 selective antagonist GW627368X. The 6-OHDA-promoted cytotoxicity was largely blocked by TG4-155, TG6-10-1 or COX-2 selective inhibitor celecoxib, but not by GW627368X. Our results suggest that PGE2 receptor EP2 is a key mediator of COX-2 activity-initiated cAMP signaling in Neuro-2a and SH-SY5Y cells following 6-OHDA treatment, and contributes to oxidopamine-mediated neurotoxicity.
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