Involvement of mitogen-activated protein kinases and protein kinase C in cadmium-induced prostaglandin E2 production in primary mouse osteoblastic cells
Involvement of mitogen-activated protein kinases and protein kinase C in cadmium-induced prostaglandin E2 production in primary mouse osteoblastic cells
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DOI：
10.1016/j.tox.2004.03.014
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发表时间：
2004-08-05
期刊：
影响因子：
4.5
通讯作者：
Komurasaki, T
中科院分区：
文献类型：
--
作者：
Miyahara, T;Katoh, T;Komurasaki, T
我们之前报道，镉（Cd）通过激活原代小鼠成骨细胞中的胞质磷脂酶A（2）（cPLA（2））和诱导环氧合酶2（COX-2）来诱导前列腺素E-2（PGE（2））生物合成。在本研究中，我们进一步研究了 Cd 产生 PGE(2) 的机制，重点关注介导前列腺素合成的主要丝裂原激活蛋白激酶 (MAPK) 亚家族、细胞外信号调节激酶 (ERK1/2 MAPK)、c-jun 氨基末端激酶 (JNK MAPK) 和 p38 MAPK 以及蛋白激酶 C (PKC) 在多种细胞中被 Cd 激活。 2 μM 及以上的 Cd 会刺激成骨细胞中 PGE(2) 的产生，并且其产生会被激酶特异性抑制剂 PD98059、SB203580、姜黄素和 calphostin C 抑制。 Calphostin C 还可以抑制佛波醇 12-肉豆蔻酸酯 13-乙酸酯 (PMA)（PMA 是 PKC 的有效激活剂）产生 PGE(2)。 PD98059 抑制 PMA 和 Cd 刺激的 PGE2 产生，表明 ERK1/2 MAPK 激活 PKC 对于 Cd 刺激的 PGE(2) 产生是必要的。此外，Cd 刺激这三种 MAPK 的磷酸化，并且还观察到 calphostin C 对 ERK1/2 MAPK 磷酸化的抑制。另一方面，Cd 使 cPLA(2) 磷酸化，并且磷酸化被 PD98059 抑制，表明 cPLA(2) 通过 ERK1/2 MAPK 被 Cd 激活，并从膜磷脂中释放 COX-2 的底物花生四烯酸 (AA)。这些结果表明，除了 PKC 和 cPLA(2) 之外，ERK1/2、p38 和 JNK MAPK 级联的激活在小鼠成骨细胞中 U 刺激的 PGE(2) 生物合成中发挥着重要作用。 (C) 2004 Elsevier Ireland Ltd. 保留所有权利。
We previously reported that cadmium (Cd) induced prostaglandin E-2 (PGE(2)) biosynthesis through the activation of cytosolic phospholipase A(2) (cPLA(2)) and induction of cyclooxygenase 2 (COX-2) in primary mouse osteoblastic cells. In the present study, we further investigated the mechanism of PGE(2) production by Cd focusing on the main mitogen-activated protein kinase (MAPK) subfamilies that mediate prostaglandin synthesis, extracellular signal-regulated kinase (ERK1/2 MAPK), c-jun-amino-terminal kinase (JNK MAPK) and p38 MAPK, and protein kinase C (PKC) which is activated by Cd in several kinds of cells. Cd at 2 muM and above stimulated PGE(2) production in osteoblastic cells and its production was inhibited by the kinase-specific inhibitors PD98059, SB203580, curcumin, and calphostin C. Calphostin C also inhibited the production of PGE(2) by phorbol 12-myristate 13-acetate (PMA), which is a potent activator of PKC. PD98059 inhibited PGE2 production stimulated by PMA as well as Cd, indicating that activation of PKC by ERK1/2 MAPK was necessary for Cd-stimulated PGE(2) production. Moreover, Cd stimulated the phosphorylation of these three MAPKs, and inhibition of the phosphorylation of ERK1/2 MAPK by calphostin C was also observed. On the other hand, Cd was found to phosphorylate cPLA(2) and the phosphorylation was inhibited by PD98059, indicating that cPLA(2) was activated by Cd through ERK1/2 MAPK and released arachidonic acid (AA), a substrate of COX-2, from membranous phospholipids. From these results, it was suggested that activation of each of the ERK1/2, p38, and JNK MAPK cascades in addition to that of PKC and cPLA(2) played an important role in the U-stimulated biosynthesis of PGE(2) in mouse osteoblastic cells. (C) 2004 Elsevier Ireland Ltd. All rights reserved.