Role for Neutral Sphingomyelinase-2 in Tumor Necrosis Factor α-Stimulated Expression of Vascular Cell Adhesion Molecule-1 (VCAM) and Intercellular Adhesion Molecule-1 (ICAM) in Lung Epithelial Cells
Role for Neutral Sphingomyelinase-2 in Tumor Necrosis Factor α-Stimulated Expression of Vascular Cell Adhesion Molecule-1 (VCAM) and Intercellular Adhesion Molecule-1 (ICAM) in Lung Epithelial Cells
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中性鞘磷脂酶 2 在肿瘤坏死因子 α 刺激肺上皮细胞中血管细胞粘附分子 1 (VCAM) 和细胞间粘附分子 1 (ICAM) 表达中的作用
DOI：
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发表时间：
2007
影响因子：
4.8
通讯作者：
Y. Hannun
中科院分区：
文献类型：
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作者：
C. Clarke;T. Truong;Y. Hannun
中性鞘磷脂酶（N-SMases）是应激诱导神经酰胺产生的主要候选物质。然而，关于克隆的N-SMase酶nSMase2的生理调控和作用的信息很少。在这项研究中，nSMase2被发现在肿瘤坏死因子α (TNF-α)的作用下，以时间和剂量依赖的方式急性易位到A549上皮细胞的质膜上。此外，TNF-α在内源性和过表达nSMase2的细胞中迅速和短暂地增加N-SMase活性。此外，nSMase2的易位受p38-α MAPK调控，而不受ERK或JNK的调控，内源性N-SMase活性的增加被p38 MAPK抑制所抵消。此外，p38-α MAPK和nSMase2都与TNF-α刺激的粘附蛋白血管细胞粘附分子-1 （VCAM）和细胞间粘附分子-1 （ICAM）的上调有关，但这在很大程度上独立于NF-κB的激活。这些数据表明p38 MAPK是nSMase2的上游调节剂，并表明nSMase2在TNF-α诱导的促炎症反应中作为粘附蛋白的调节剂发挥作用。
Neutral sphingomyelinases (N-SMases) are major candidates for stress-induced ceramide production. However, there is little information on the physiological regulation and roles of the cloned N-SMase enzyme, nSMase2. In this study, nSMase2 was found to translocate acutely to the plasma membrane of A549 epithelial cells in response to tumor necrosis factor α (TNF-α) in a time- and dose-dependent manner. Additionally, TNF-α increased N-SMase activity rapidly and transiently both endogenously and in cells overexpressing nSMase2. Furthermore, the translocation of nSMase2 was regulated by p38-α MAPK, but not ERK or JNK, and the increase in endogenous N-SMase activity was abrogated by p38 MAPK inhibition. In addition, both p38-α MAPK and nSMase2 were implicated in the TNF-α-stimulated up-regulation of the adhesion proteins vascular cell adhesion molecule-1 (VCAM) and intercellular adhesion molecule-1 (ICAM), but this was largely independent of NF-κB activation. These data reveal p38 MAPK as an upstream regulator of nSMase2 and indicate a role for nSMase2 in pro-inflammatory responses induced by TNF-α as a regulator of adhesion proteins.