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 (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.
Ferrero
E
E
Laboratory of Tumor Immunology, Scientific Institute San Raffaele, Italy.
Villa
A
A
Ferrero
M E
ME
Toninelli
E
E
Bender
J R
JR
Pardi
R
R
Zocchi
M R
MR
D000470:Alkaloids / Q000494:pharmacology; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism*; D016227:Benzoquinones; D002199:Capillary Permeability / Q000187:drug effects*; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D002451:Cell Compartmentation; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019084:Fluorescent Antibody Technique, Indirect; D015870:Gene Expression; D006801:Humans; D047029:Lactams, Macrocyclic; D010766:Phosphorylation; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D047428:Protein Kinase Inhibitors; D011809:Quinones / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D017828:Rifabutin / Q000031:analogs & derivatives; D019311:Staurosporine; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014471:Umbilical Veins
D000470:Alkaloids; D015214:Antigens, Differentiation, Myelomonocytic; D016227:Benzoquinones; D015815:Cell Adhesion Molecules; D004791:Enzyme Inhibitors; D047029:Lactams, Macrocyclic; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D047428:Protein Kinase Inhibitors; D011809:Quinones; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D017828:Rifabutin; C020754:herbimycin; D019311:Staurosporine