Extracellular signal-regulated kinase and p38 mitogen-activated protein kinase mediate macrophage proliferation induced by oxidized low-density lipoprotein
Extracellular signal-regulated kinase and p38 mitogen-activated protein kinase mediate macrophage proliferation induced by oxidized low-density lipoprotein
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DOI：
10.1016/j.atherosclerosis.2004.05.019
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发表时间：
2004-10-01
期刊：
影响因子：
5.3
通讯作者：
Araki, E
中科院分区：
文献类型：
--
作者：
Senokuchi, T;Matsumura, T;Araki, E
我们先前报道，氧化低密度脂蛋白(Ox-LDL)通过PKC诱导粒细胞/巨噬细胞集落刺激因子(GM-CSF)的表达，导致磷脂酰肌醇-3激酶(PI-3K)的激活，对巨噬细胞的增殖起重要作用[J Biol Chem 275(2000)5810]。本研究旨在阐明细胞外信号调节蛋白1/2(ERK1/2)和p38MAPK在氧化低密度脂蛋白(Ox-LDL)诱导的巨噬细胞增殖中的作用。用[H-3]胸腺嘧啶核苷掺入法和细胞计数法检测，MEK1/2抑制剂PD98059或U0126和p38 MAPK抑制剂SB203580或SB202190可显著抑制OX-LDL诱导的小鼠腹膜巨噬细胞的增殖。氧化低密度脂蛋白诱导的巨噬细胞产生GM-CSF可被MEK1/2抑制剂抑制，但不能被p38 MAPK抑制剂抑制，而重组GM-CSF诱导的巨噬细胞增殖可被p38 MAPK抑制剂抑制，但被MEK1/2抑制剂促进。SB203580可显著抑制重组GM-CSF诱导的PI-3K活化和Akt磷酸化，而PD98059则可增强该作用。我们的结果提示ERK1/2在GM-CSF产生之前参与了Ox-LDL诱导的巨噬细胞增殖的信号通路，而p38MAPK在GM-CSF释放后参与了信号通路。因此，MAPK在氧化低密度脂蛋白诱导的巨噬细胞增殖中的重要性得到了证实，MAPK级联反应的控制可能成为治疗动脉粥样硬化的潜在靶点。(C)2004爱思唯尔爱尔兰有限公司。保留所有权利。
We previously reported that oxidized low-density lipoprotein (Ox-LDL)-induced expression of granulocyte/macrophage colony-stimulating factor (GM-CSF) via PKC, leading to activation of phosphatidylinositol-3 kinase (PI-3K), was important for macrophage proliferation [J Biol Chem 275 (2000) 5810]. The aim of the present study was to elucidate the role of extracellular-signal regulated kinase 1/2 (ERK1/2) and of p38 MAPK in Ox-LDL-induced macrophage proliferation. Ox-LDL-induced proliferation of mouse peritoneat macrophages assessed by [H-3]thymidine incorporation and cell counting assays was significantly inhibited by MEK1/2 inhibitors, PD98059 or U0126, and p38 MAPK inhibitors, SB203580 or SB202190, respectively. Ox-LDL-induced GM-CSF production was inhibited by MEK1/2 inhibitors but not by p38 MAPK inhibitors in mRNA and protein levels, whereas recombinant GM-CSF-induced macrophage proliferation was inhibited by p38 MAPK inhibitors but enhanced by MEK1/2 inhibitors. Recombinant GM-CSF-induced PI-3K activation and Akt phosphorylation were significantly inhibited by SB203580 but enhanced by PD98059. Our results suggest that ERK1/2 is involved in Ox-LDL-induced macrophage proliferation in the signaling pathway before GM-CSF production, whereas p38 MAPK is involved after GM-CSF release. Thus, the importance of MAPKs in Ox-LDL-induced macrophage proliferation was confirmed and the control of MAPK cascade could be targeted as a potential treatment of atherosclerosis. (C) 2004 Elsevier Ireland Ltd. All rights reserved.