TNF α increases endothelial permeability via its effect on redistribution of VE cadherin induced by P38 MAPK activity

Objective: To study the influence of tumor necrosis factor alpha (TNFa) on endothelial permeability and its mechanism. Methods: Human umbilical vein endothelial cell (HUVEC) monolayer permeability was measured by enzyme-linked immunosorbent assay for biotin-labeled albumin. Immunofluorescence, laser confocal microscopy, and Western immunoblotting were used to assess vascular endothelial (VE) cadherin distribution. Mitogen-activated protein kinase (MAPK) activity was determined by using functional kinase assay and was inhibited with the compounds SB202190 (P38 inhibitor) and PD98059 (ERK inhibitor). Results: TNFα significantly increased endothelial permeability and reduced the expression of membrane-associated VE cadherin. Furthermore, TNFα activated P38 MAPK and ERK MAPK compared with controls (P<0.05). Interestingly, SB202190 significantly reduced the effect of TNFα on endothelial permeability and cell-surface VE cadherin expression, but PD98059 did not. Conclusion: TNFα increases endothelial permeability by activating P38 MAPK and then inhibiting the expression of VE cadherin and its redistribution on HUVEC.