Sphingosine kinase-1 mediates TNF-α-induced MCP-1 gene expression in endothelial cells:: upregulation by oscillatory flow
Sphingosine kinase-1 mediates TNF-α-induced MCP-1 gene expression in endothelial cells:: upregulation by oscillatory flow
复制标题
DOI：
10.1152/ajpheart.01101.2003
复制
发表时间：
2004-10-01
影响因子：
4.8
通讯作者：
Kunsch, C
中科院分区：
文献类型：
--
作者：
Chen, XL;Grey, JY;Kunsch, C
动脉粥样硬化是一种局灶性炎性疾病，并且优先发生在低流体剪切应力和振荡流的区域，而动脉粥样硬化的风险在高流体剪切应力和稳定层流的区域中降低。鞘氨醇激酶-1（SphK 1）催化鞘氨醇转化为鞘氨醇-1磷酸（S1 P），S1 P是一种鞘脂代谢产物，在血管生成、炎症和细胞生长中起重要作用。在本研究中，我们证明，与静态培养的内皮细胞相比，将人主动脉内皮细胞暴露于振荡流（剪切应力，+/-5 dyn/cm（2），持续48 h）导致SphK 1 mRNA水平显著增加。相反，层流（剪切应力，20达因/厘米（2）48小时）降低SphK 1 mRNA水平。我们进一步研究了SphK 1在TNF-α诱导的炎症基因表达中的作用，如单核细胞趋化蛋白-1（MCP-1）和VCAM-1，通过使用特异性针对SphK 1的小干扰RNA（siRNA）。用SphK 1 siRNA处理内皮细胞抑制TNF-α诱导的MCP-1 mRNA水平、MCP-1蛋白分泌和p38 MAPK活化的增加。SphK 1 siRNA还抑制TNF-α诱导的VCAM-1蛋白的细胞表面表达，但不抑制ICAM-1蛋白的表达。内皮细胞暴露于S1 P导致MCP-1蛋白分泌和MCP-1 mRNA水平的增加以及NF-κ B介导的转录活性的激活。用p38 MAPK抑制剂SB-203580处理内皮细胞抑制S1 P诱导的MCP-1蛋白分泌。这些数据表明，SphK 1通过p38 MAPK依赖性途径介导TNF-α诱导的MCP-1基因表达，并可能参与血管系统中振荡流介导的促炎信号通路。
Atherosclerosis is a focal inflammatory disease and preferentially occurs in areas of low fluid shear stress and oscillatory flow, whereas the risk of atherosclerosis is decreased in regions of high fluid shear stress and steady laminar flow. Sphingosine kinase-1 (SphK1) catalyzes the conversion of sphingosine to sphingosine-1 phosphate (S1P), a sphingolipid metabolite that plays important roles in angiogenesis, inflammation, and cell growth. In the present study, we demonstrated that exposure of human aortic endothelial cells to oscillatory flow ( shear stress, +/-5 dyn/cm(2) for 48 h) resulted in a marked increase in SphK1 mRNA levels compared with endothelial cells kept in static culture. In contrast, laminar flow ( shear stress, 20 dyn/cm(2) for 48 h) decreased SphK1 mRNA levels. We further investigated the role of SphK1 in TNF-alpha-induced expression of inflammatory genes, such as monocyte chemoattractant protein-1 (MCP-1) and VCAM-1 by using small interfering RNA ( siRNA) specifically for SphK1. Treatment of endothelial cells with SphK1 siRNA suppressed TNF-alpha-induced increase in MCP-1 mRNA levels, MCP-1 protein secretion, and activation of p38 MAPK. SphK1 siRNA also inhibited TNF-alpha-induced cell surface expression of VCAM-1, but not ICAM-1, protein. Exposure of endothelial cells to S1P led to an increase in MCP-1 protein secretion and MCP-1 mRNA levels and activation of NF-kappaB-mediated transcriptional activity. Treatment of endothelial cells with the p38 MAPK inhibitor SB-203580 suppressed S1P-induced MCP-1 protein secretion. These data suggest that SphK1 mediates TNF-alpha-induced MCP-1 gene expression through a p38 MAPK-dependent pathway and may participate in oscillatory flow-mediated proinflammatory signaling pathway in the vasculature.