Involvement of COX-1 and up-regulated prostaglandin E synthases in phosphatidylserine liposome-induced prostaglandin E2 production by microglia
Involvement of COX-1 and up-regulated prostaglandin E synthases in phosphatidylserine liposome-induced prostaglandin E2 production by microglia
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DOI：
10.1016/j.jneuroim.2005.11.008
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发表时间：
2006-03-01
影响因子：
3.3
通讯作者：
Nakanishi, H
中科院分区：
文献类型：
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作者：
Zhang, J;Fujii, S;Nakanishi, H
小胶质细胞通过磷脂酰丝氨酸(PS)介导的识别吞噬凋亡细胞后，分泌前列腺素E-2(PGE(2))，这是中枢神经系统中一种有效的抗炎分子。尽管PGE(2)具有临床意义，但通过吞噬凋亡细胞产生PGE(2)的机制尚不清楚。在本研究中，我们使用PS脂质体来阐明小胶质细胞产生PGE(2)的吞噬途径，因为PS脂质体模拟了凋亡细胞对小胶质细胞/巨噬细胞的影响。原代培养的大鼠小胶质细胞培养上清液中PGE(2)浓度在PS脂质体处理组显著升高，而磷脂酰胆碱脂质体处理组无明显变化。B类清道夫受体(SR-B)的特异性配体高密度脂蛋白显著抑制PS脂质体诱导的PGE(2)的产生。PS脂质体立即被小胶质细胞吞噬，并被分选为内/溶酶体。脂多糖(LPS)诱导环氧合酶(COX)-2和膜结合型前列腺素E合成酶-1(mPGES-1)，PS脂质体则不诱导。而与COX-1功能偶联的mPGES-2和胞内PGES(CPGES)在PS脂质体或脂多糖作用下表达上调。此外，选择性COX-1抑制剂消炎痛显著抑制PS脂质体诱导的PGE(2)的产生，而选择性COX-2抑制剂NS-398不能抑制PS脂质体诱导的PGE(2)的产生。PS脂质体以SR-BI非依赖性的方式诱导p44/p42细胞外信号调节蛋白激酶(ERK)激活，但不诱导p38丝裂原活化蛋白激酶的激活。这些观察结果有力地表明，优先与COX-1，尤其是mPGES-2偶联的末端PGEs的上调，在PS脂质体诱导小胶质细胞产生PGE(2)的过程中起着关键作用。虽然SR-BI在PS脂质体诱导的PGE(2)产生中起重要作用，但其他PS识别受体，可能是PS特异性受体，也可以在PS脂质体处理后通过转导包括p44/p42ERK在内的细胞内信号来促进PGE(2)的产生。(C)2005 Elsevier B.V.保留所有权利。
After engulfment of apoptotic cells through phosphatidylserine (PS)-mediated recognition, microglia secrete prostaglandin E-2 (PGE(2)), a potent anti-inflammatory molecule in the central nervous system. Despite the clinical significance, the mechanism underlying PGE(2) production by phagocytosis of apoptotic cells is poorly understood. In the present study, we used PS liposomes to elucidate the phagocytic pathway for PGE(2) production in microglia, because PS liposomes mimic the effects of apoptotic cells on microglia/macrophages. The level of PGE(2) in the culture medium of primary cultured rat microglia was significantly increased by PS liposomes treatment but not by phosphatidylcholine liposomes treatment. The specific ligand for class B scavenger receptor (SR-B), high density lipoprotein, significantly suppressed PS liposome-induced PGE(2) production. PS liposomes were immediately phagocytosed by microglia and sorted to endosomes/lysosomes. Cyclooxygenase (COX)-2 and membrane-bound prostaglandin E synthase-1 (mPGES-1) were induced by treatment with lipopolysaccharide (LPS) but not with PS liposomes. On the other hand, mPGES-2 and cytosolic PGES (cPGES) that are functionally coupled with COX-1 were upregulated after treatment with PS liposomes or LPS. Furthermore, PS liposome-induced PGE(2) production was significantly suppressed by indomethacin, a preferential COX-1 inhibitor, but not by NS-398, a selective COX-2 inhibitor. PS liposomes induced activation of p44/p42 extracellular signal-regulated kinase (ERK) but not p38 mitogen-activated protein kinase in SR-BI independent manner. These observations strongly suggest that the up-regulation of terminal PGESs that are preferentially coupled with COX-1, especially mPGES-2, plays the pivotal role in PS liposome-induced PGE(2) production by microglia. Although SR-BI plays an essential role in PS liposome-induced PGE(2) production, other PS-recognizing receptors, possibly PS-specific receptor, could also promote PGE(2) production by transducing intracellular signals including p44/p42 ERK after PS liposomes treatment. (C) 2005 Elsevier B.V. All rights reserved.