Oxidized phospholipids induce expression of human heme oxygenase-1 involving activation of cAMP-responsive element-binding protein
Oxidized phospholipids induce expression of human heme oxygenase-1 involving activation of cAMP-responsive element-binding protein
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DOI：
10.1074/jbc.m304103200
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发表时间：
2003-12-19
影响因子：
4.8
通讯作者：
Leitinger, N
中科院分区：
文献类型：
--
作者：
Krönke, G;Bochkov, VN;Leitinger, N
血红素加氧酶-1（HO- 1）催化血红素降解的限速步骤，保护免受氧化应激，并显示出有效的抗炎作用。在炎症和细胞凋亡过程中产生的氧化磷脂通过诱导包括HO- 1在内的几种基因的表达来调节炎症反应。我们研究了氧化型1-棕榈酰-2-花生四烯酰- sn-甘油-3-磷酸胆碱（OxPAPC）诱导人脐静脉内皮细胞HO- 1基因表达的信号通路和转录事件。OxPAPC以时间和浓度依赖性方式上调HO- 1 mRNA和蛋白，而促炎剂如TNF-α和脂多糖在人脐静脉内皮细胞中不显著诱导HO- 1表达。参与OxPAPC介导的HO- 1诱导的信号通路包括蛋白激酶A和C，以及促分裂原活化蛋白激酶p38和ERK。cAMP反应元件结合蛋白（CREB）通过这些途径响应于OxPAPC处理而磷酸化，并且CREB的显性负突变体的表达抑制了人血红素加氧酶-1启动子驱动的荧光素酶报告基因构建体的OxPAPC诱导的活性。我们鉴定了cAMP应答元件和Maf识别元件参与OxPAPC对HO- 1启动子的转录激活。在凝胶迁移分析中，我们观察到OxPAPC处理后CREB与cAMP反应元件的结合。脂质氧化产物通过CREB诱导HO- 1表达可能是限制炎症和相关组织损伤的反馈机制。
Heme oxygenase- 1 ( HO- 1) catalyzes the rate- limiting step in heme degradation, protects against oxidative stress, and shows potent anti- inflammatory effects. Oxidized phospholipids, which are generated during inflammation and apoptosis, modulate the inflammatory response by inducing the expression of several genes including HO- 1. Here we investigated the signaling pathways and transcriptional events involved in the induction of HO- 1 gene expression by oxidized 1- palmitoyl-2- arachidonoyl- sn- glycero- 3- phosphorylcholine ( OxPAPC) in human umbilical vein endothelial cells. OxPAPC up- regulated HO- 1 mRNA and protein in a time- and concentration- dependent manner, whereas pro- inflammatory agents like TNF-alpha and lipopolysaccharide did not significantly induce HO- 1 expression in human umbilical vein endothelial cells. Signaling pathways involved in the OxPAPC- mediated HO- 1 induction included protein kinases A and C, as well as the mitogen-activated protein kinases p38 and ERK. The cAMP-responsive element- binding protein ( CREB) was phosphorylated via these pathways in response to OxPAPC treatment and expression of a dominant- negative mutant of CREB inhibited OxPAPC- induced activity of a human heme oxygenase- 1 promoter- driven luciferase reporter construct. We identified a cAMP- responsive element and a Maf recognition element to be involved in the transcriptional activation of the HO- 1 promoter by OxPAPC. In gel shift assays we observed binding of CREB to the cAMP- responsive element after OxPAPC treatment. Induction of HO- 1 expression by lipid oxidation products via CREB may represent a feedback mechanism to limit inflammation and associated tissue damage.