Lithium Chloride Increases COX-2 Expression and PGE2 Production in a Human Granulosa-Lutein SVOG Cell Line Via a GSK-3β/β-Catenin Signaling Pathway
Lithium Chloride Increases COX-2 Expression and PGE2 Production in a Human Granulosa-Lutein SVOG Cell Line Via a GSK-3β/β-Catenin Signaling Pathway
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DOI：
10.1210/en.2017-00287
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发表时间：
2017-09-01
期刊：
影响因子：
4.8
通讯作者：
Yang, Gongshe
中科院分区：
文献类型：
--
作者：
Bai, Long;Chang, Hsun-Ming;Yang, Gongshe
氯化锂（LiCl）被广泛用于治疗双相情感障碍，并与生殖不良反应的较高发生率相关。环氧合酶(COX)-2及其衍生物前列腺素E2 （PGE2）在人的排卵过程中起调节作用。LiCl是否通过调节人卵巢中COX2的表达和PGE2的产生而影响排卵在很大程度上仍是未知的。本研究的目的是探讨LiCl对人颗粒叶黄素（hGL）细胞中COX-2表达和PGE2生成的影响及其作用机制。永生化和原代hGL细胞均作为研究模型。使用双抑制方法，我们的研究结果表明，LiCl通过抑制糖原合成酶激酶-3 β [GSK-3 β （GSK-3 β的磷酸化）]的活性和细胞外信号调节激酶1/2 （ERK1/2）的激活来启动hGL细胞作用，但不影响蛋白激酶B或cAMP反应元件结合蛋白信号传导。此外，GSK-3 β的磷酸化，而不是ERK1/2的磷酸化，导致β -连环蛋白的稳定和核定位。此外，敲低β -catenin或GSK-3 β均可逆转licl诱导的COX-2表达上调。这些结果表明，LiCl通过典型的GSK-3 β / β -catenin信号通路上调hGL细胞中COX-2的表达和随后的PGE2的产生。
Lithium chloride (LiCl) is widely prescribed for the treatment of bipolar disorders and is associated with a higher incidence of reproductive adverse effects. Cyclooxygenase (COX)-2 and its derivative, prostaglandin E2 (PGE2), play regulatory roles in the human ovulatory process. Whether LiCl affects ovulation by regulating COX2 expression and PGE2 production in the human ovary is still largely unknown. The aim of this study was to investigate the effect of LiCl on the expression of COX-2 and production of PGE2 in human granulosa-lutein (hGL) cells, as well as the mechanisms underlying this effect. Both immortalized and primary hGL cells were used as research models. Using dual inhibition approaches, our results show that LiCl initiates the hGL cellular action by inhibiting the activity of glycogen synthase kinase-3 beta [GSK-3 beta (phosphorylation of GSK-3 beta)] and activation of extracellular signal-regulated kinase 1/2 (ERK1/2), but not by affecting protein kinase B or cAMP response element binding protein signaling. Additionally, the phosphorylation of GSK-3 beta, but not ERK1/2, resulted in the stabilization and nuclear localization of beta-catenin. Furthermore, knockdown of either beta-catenin or GSK-3 beta reversed the LiCl-induced upregulation of COX-2 expression. These results indicate that LiCl upregulates the expression of COX-2 and the subsequent production of PGE2 through the canonical GSK-3 beta/beta-catenin signaling pathway in hGL cells.