Actin polymerization in macrophages in response to oxidized LDL and apoptotic cells: Role of 12/15-lipoxygenase and phosphoinositide 3-kinase
Actin polymerization in macrophages in response to oxidized LDL and apoptotic cells: Role of 12/15-lipoxygenase and phosphoinositide 3-kinase
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DOI：
10.1091/mbc.e03-02-0063
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发表时间：
2003-10-01
影响因子：
3.3
通讯作者：
Witztum, JL
中科院分区：
文献类型：
--
作者：
Miller, YI;Worrall, DS;Witztum, JL
丝状F-肌动蛋白的形成驱动许多细胞过程，包括吞噬作用和细胞铺展。我们最近报道，小鼠巨噬细胞12/15-脂氧合酶（12/15-LO）的活性促进F-肌动蛋白的形成在丝状伪足在吞噬凋亡细胞。氧化低密度脂蛋白（OxLDL）也刺激强大的F-肌动蛋白的形成和巨噬细胞的扩散。然而，不像凋亡细胞，氧化低密度脂蛋白没有引起特定的易位的12/15-LO的细胞膜，无论是在巨噬细胞，也不是在GFP-15 LO转染的COS-7细胞。此外，通过特异性抑制剂或通过12/15-LO基因破坏抑制巨噬细胞中的12/15-LO活性并不影响OxLDL诱导的肌动蛋白聚合。在LDL修饰模型OxLDL中，通过与15 LO过表达成纤维细胞孵育修饰的LDL在引发F-肌动蛋白反应方面与OxLDL一样活跃。众所周知，这种LDL修饰产生最低限度修饰的LDL（mmLDL），其具有生物活性并携带与12/15-LO催化产生的脂质氧化产物类似的脂质氧化产物。mmLDL激活磷酸肌醇3-激酶（PI 3 K），PI 3 K抑制剂消除mmLDL诱导的巨噬细胞扩散。我们推测，OxLDL和mmLDL可能有助于氧化脂质的巨噬细胞膜，从而模拟细胞内的12/15-LO活动，这导致不受控制的肌动蛋白聚合和巨噬细胞的细胞骨架的变化。
Formation of filamentous F-actin drives many cellular processes, including phagocytosis and cell spreading. We have recently reported that mouse macrophage 12/15-lipoxygenase (12/15-LO) activity promotes F-actin formation in filopodia during phagocytosis of apoptotic cells. Oxidized low-density lipoprotein (OxLDL) also stimulates robust F-actin formation and spreading of macrophages. However, unlike apoptotic cells, OxLDL did not cause specific translocation of 12/15-LO to the cell membrane, neither in macrophages nor in GFP-15LO-transfected COS-7 cells. Moreover, inhibition of 12/15-LO activity in macrophages by a specific inhibitor or by 12/15-LO gene disruption did not affect OxLDL-induced actin polymerization. Among LDL modifications modeling OxLDL, LDL modified by incubation with 15LO-overexpressing fibroblasts was as active in eliciting F-actin response as was OxLDL. This LDL modification is well known to produce minimally modified LDL (mmLDL), which is bioactive and carries lipid oxidation products similar to those produced by 12/15-LO catalysis. MmLDL activated phosphoinositide 3-kinase (PI3K), and PI3K inhibitors abolished mmLDL-induced macrophage spreading. We hypothesize that OxLDL and mmLDL may contribute oxidized lipids to the macrophage cell membrane and thereby mimic intracellular 12/15-LO activity, which leads to uncontrolled actin polymerization and dramatic cytoskeletal changes in macrophages.