TUMOR-NECROSIS-FACTOR ALPHA-INDUCED VASCULAR LEAKAGE INVOLVES PECAM1 PHOSPHORYLATION

Herein we show that exposure of human umbilical vein endothelial cells to tumor necrosis factor alpha (TNF alpha) led to platelet endothelia l cell adhesion molecule-1 (PECAM1) surface redistribution, disruption of cytoskeleton connections, and increased PECAM1 phosphorylation, ac companied by increased permeability to macromolecules. The in vitro us e of inhibitors of tyrosine or serine-threonine kinases could prevent both PECAM1 surface redistribution and the increase in permeability in duced by the cytokine. In vivo administration of lavendustin A, a natu ral tyrosine kinase inhibitor, protected endothelial cells from TNF al pha-dependent vascular leakage in mouse liver, We propose that the inv olvement of PECAM1 in TNF alpha-mediated effects on vascular permeabil ity may depend on a dynamically regulated cytoskeletal association, re lated to the degree of PECAM1 phosphorylation.