Tumor necrosis factor alpha-induced vascular leakage involves PECAM1 phosphorylation.

Abstract

Herein we show that exposure of human umbilical vein endothelial cells to tumor necrosis factor alpha (TNFalpha) led to platelet endothelial cell adhesion molecule-1 (PECAM1) surface redistribution, disruption of cytoskeleton connections, and increased PECAM1 phosphorylation, accompanied by increased permeability to macromolecules. The in vitro use of inhibitors of tyrosine or serine-threonine kinases could prevent both PECAM1 surface redistribution and the increase in permeability induced by the cytokine. In vivo administration of lavendustin A, a natural tyrosine kinase inhibitor, protected endothelial cells from TNFalpha-dependent vascular leakage in mouse liver. We propose that the involvement of PECAM1 in TNFalpha-mediated effects on vascular permeability may depend on a dynamically regulated cytoskeletal association, related to the degree of PECAM1 phosphorylation.