Prostaglandin E2 is an enhancer of interleukin-1β-induced expression of membrane-associated prostaglandin E synthase in rheumatoid synovial fibroblasts
Prostaglandin E2 is an enhancer of interleukin-1β-induced expression of membrane-associated prostaglandin E synthase in rheumatoid synovial fibroblasts
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DOI：
10.1002/art.11261
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发表时间：
2003-10-01
影响因子：
--
通讯作者：
Kawai, S
中科院分区：
文献类型：
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作者：
Kojima, F;Naraba, H;Kawai, S
客观的。膜相关前列腺素 E 合酶 (mPGES) 是最近发现的花生四烯酸级联的末端酶，可将类风湿性关节炎滑膜成纤维细胞 (RASF) 中的 PGH(2) 转化为 PGE(2)。本研究旨在探讨调节 mPGES 表达的因素。方法。 RASF 使用白细胞介素 1β (IL-1β)、吲哚美辛、NS-398、罗非昔布或美洛昔康治疗。还研究了 PGE(2) 和选择性激动剂对 PGE(2) 受体亚型（EP1、EP2、EP3 和 EP4）的影响。分别通过 Northern 印迹分析和蛋白质印迹分析测量 mPGES 信使 RNA (mRNA) 和蛋白质的表达。通过逆转录酶-聚合酶链式反应测定RASF中EP受体mRNA的表达。通过酶联免疫吸附测定法测量 PGE2 和 cAMP 的产生。结果。添加吲哚美辛、NS-398、罗非考昔或美洛昔康可减弱 IL-1β 刺激的 RASF 中 mPGES mRNA 和蛋白质表达的增强。 PGE(2) 可逆转这种表达减少。罗非考昔可降低 IL-1β 诱导的 PGES 活性（通过 PGH(2) 转化为 PGE(2) 来测量）。在 RASF 中检测到 EP2 和 EP4 受体 mRNA。 EP2 和 EP4 激动剂以及 PGE2 恢复了罗非昔布对 mPGES 表达的抑制作用。 PGE2 的作用被毛喉素（腺苷酸环化酶的直接激活剂）模仿。 IL-1β可增加细胞内cAMP，而罗非考昔则可抑制细胞内cAMP。结论。 PGE(2) 通过 EP2/EP4 受体增强 mPGES 表达并增加 cAMP，可能在 RA 患者的关节炎症中发挥重要作用。环氧合酶 2 (COX-2) 抑制剂似乎不仅通过直接抑制 COX-2 来减少 PGE2 的产生，还通过减少活化的 RASF 中 mPGES 的表达来减少 PGE2 的产生。
Objective. Membrane-associated prostaglandin E synthase (mPGES) is a recently identified terminal enzyme of the arachidonic acid cascade, which converts PGH(2) to PGE(2) in rheumatoid arthritis synovial fibroblasts (RASFs). This study was undertaken to investigate factors regulating the expression of mPGES.Methods. RASFs were treated with interleukin-1beta (IL-1beta), indomethacin, NS-398, rofecoxib, or meloxicam. The effects of PGE(2) and selective agonists for PGE(2) receptor subtypes (EP1, EP2, EP3, and EP4) were also studied. Expression of mPGES messenger RNA (mRNA) and protein was measured by Northern and Western blot analysis, respectively. EP receptor mRNA expression in RASFs was determined by reverse transcriptase-polymerase chain reaction. Production of PGE2 and cAMP was measured by enzyme-linked immunosorbent assay.Results. The enhanced expression of mPGES mRNA and protein in IL-1beta-stimulated RASFs was attenuated by the addition of indomethacin, NS-398, rofecoxib, or meloxicam. This reduction of expression was reversed by PGE(2). IL-1beta-induced PGES activity, measured by conversion of PGH(2) to PGE(2), was decreased by rofecoxib. EP2 and EP4 receptor mRNA was detected in RASFs. EP2 and EP4 agonists, as well as PGE2, restored the inhibitory effect of rofecoxib on mPGES expression. The effect of PGE2 was mimicked by forskolin, a direct activator of adenylate cyclase. Intracellular cAMP was increased by IL-1beta and was inhibited by rofecoxib.Conclusion. Enhancement of mPGES expression by PGE(2) via the EP2/EP4 receptors with an increase in cAMP may play an important role in articular inflammation in patients with RA. It also seems that cyclooxygenase 2 (COX-2) inhibitors decrease PGE2 production not only by direct inhibition of COX-2, but also by reducing mPGES expression in activated RASFs.