The role of p38 map kinase in tumor necrosis factor-induced redistribution of vascular endothelial cadherin and increased endothelial permeability
The role of p38 map kinase in tumor necrosis factor-induced redistribution of vascular endothelial cadherin and increased endothelial permeability
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DOI：
10.1097/00024382-200207000-00015
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发表时间：
2002-07-01
期刊：
影响因子：
3.1
通讯作者：
Turnage, RH
中科院分区：
文献类型：
--
作者：
Nwariaku, FE;Chang, JP;Turnage, RH
肿瘤坏死因子α(TNFpha)增加内皮通透性的机制尚不清楚。血管内皮细胞(VE)钙粘附素(Cadherin 5)是内皮细胞单层完整性的重要因素。本研究的目的是确定肿瘤坏死因子α对VE-钙粘蛋白细胞表面表达的影响，并确定参与肿瘤坏死因子诱导的钙粘蛋白表达变化的信号通路。采用生物素标记白蛋白的酶联免疫吸附试验测定人脐静脉内皮细胞单层通透性。免疫荧光、激光共聚焦显微镜和免疫印迹法检测VE钙粘蛋白的分布。丝裂原活化蛋白激酶(MAPK)活性用功能激酶法测定，化合物SB202190和PD98059可抑制MAPK活性。与对照组相比，肿瘤坏死因子α显著增加细胞通透性，并诱导p38和ERK MAPK激活。这些变化与膜相关的VE钙粘附素的丢失有关。抑制p38而不是ERK MAPK显着降低了TNFa对内皮细胞通透性和细胞表面VE钙粘蛋白表达的影响。P38MAP激活似乎是一个重要的上游信号事件，与内皮通透性增加和血管内皮细胞钙粘附素重新分布有关。
The mechanism by which tumor necrosis factor alpha (TNFalpha) increases endothelial permeability is unclear. Vascular endothelial (VE) cadherin (cadherin 5) is an important contributor to endothelial monolayer integrity. The purpose of our study was to determine the effect of TNFalpha on VE-cadherin cell-surface expression and to identify the signaling pathways involved in TNF-induced changes in cadherin expression. Human umbilical vein endothelial cell monolayer permeability was measured by enzyme-linked immunosorbent assay for biotin-labeled albumin. Immunofluorescence, laser confocal microscopy, and Western immunobloting were used to assess VE cadherin distribution. Mitogen-activated protein kinase (MAPK) activity was determined using functional kinase assays and was inhibited with the compounds SB202190 and PD98059. TNFalpha significantly increased permeability and induced p38 and ERK MAPK activation compared with controls P < 0.05. These changes were associated with a loss of membrane-associated VE cadherin. Inhibition of p38 but not ERK MAPK significantly reduced the effect of TNFa on endothelial permeability and cell-surface VE cadherin expression. p38 MAP kinase activation appears to be an important upstream signaling event associated with increased endothelial permeability and vascular endothelial cadherin redistribution.