Prostaglandin E2 induces apoptosis in cultured rat microglia
Prostaglandin E2 induces apoptosis in cultured rat microglia
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DOI：
10.1016/j.brainres.2014.05.011
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发表时间：
2014-06
期刊：
影响因子：
2.9
通讯作者：
T. Nagano;S. H. Kimura;M. Takemura
中科院分区：
文献类型：
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作者：
T. Nagano;S. H. Kimura;M. Takemura
前列腺素E2（PGE 2）在调节小胶质细胞功能中起关键作用，包括通过EP 2的迁移和吞噬作用，其增加细胞内环磷酸腺苷（AMP）浓度。在本研究中，我们发现PGE 2降低了小胶质细胞的细胞活力。PGE 2抑制3-（4，5-二甲基噻唑-2-噻唑基）-2，5-二苯基溴化四氮唑（MTT）还原，增加乳酸脱氢酶释放、脱氧核糖核酸断裂和聚（ADP-核糖）聚合酶裂解，提示PGE 2诱导这些细胞凋亡。EP 2激动剂布他前列素和EP 4激动剂PGE 1alcohol也能诱导细胞凋亡，而EP 1激动剂17-phenyl trinor PGE 2或EP 3激动剂硫前列酮在10− 6 M浓度下不能诱导细胞凋亡。另一方面，EP 1-EP 4拮抗剂SC-51322、AH 6809、L-798106或GW 627368 X，高达10− 5 M时，不影响PGE 2对MTT还原的降低。在10− 6 M浓度下，布他前列素可诱导细胞内cAMP蓄积，而17-苯基三去甲基前列腺素E2、硫前列酮或前列腺素E1醇则不能诱导细胞内cAMP蓄积。此外，我们以前报道过，AH 6809逆转了PGE 2诱导的细胞内cAMP积累。除了EP受体外，前列腺素转运蛋白也被认为是靶点之一，但其抑制剂溴甲酚绿色或U-46619高达10− 5 M并不影响PGE 2对MTT还原的降低。这些结果表明，PGE 2诱导小胶质细胞凋亡不依赖于细胞内cAMP浓度，PGE 2诱导的凋亡和小胶质细胞功能的调节之间存在不同的机制。
Prostaglandin E2(PGE2) plays a critical role in the modulation of microglial function including migration and phagocytosis through EP2, which increases intracellular cyclic adenosine monophosphate (AMP) concentration. In the present study, we found that PGE2reduces cell viability in microglia. PGE2decreased 3-(4,5-dimethylthiazol-2-thiazolyl)-2,5-diphenyltetrazolium bromide (MTT) reduction and increased lactate dehydrogenase release, deoxyribonucleic acid fragmentation, and poly(ADP-ribose) polymerase cleavage after 24 h incubation, suggesting that PGE2induces apoptosis in these cells. An EP2 agonist, butaprost, and an EP4 agonist, PGE1alcohol, also induced apoptosis, while an EP1 agonist, 17-phenyl trinor PGE2, or an EP3 agonist, sulprostone, at 10−6M did not. On the other hand, EP1–EP4 antagonists, SC-51322, AH6809, L-798106, or GW627368X, up to 10−5M did not affect the decrease in MTT reduction by PGE2. Intracellular cyclic AMP accumulation was induced by butaprost, but not 17-phenyl trinor PGE2, sulprostone, or PGE1alcohol at 10−6M. Additionally, we previously reported that PGE2-induced intracellular cyclic AMP accumulation was reversed by AH6809. Besides EP receptors, one of other targets was thought to be prostaglandin transporter, but its inhibitors, bromocresol green or U-46619 up to 10−5M did not affect the decrease in MTT reduction by PGE2. These results suggest that PGE2induces apoptosis in microglia independent of intracellular cyclic AMP concentration, and there are different mechanisms between PGE2-induced apoptosis and the modulation of microglial function.