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Tumor Necrosis Factor -induced Vascular Leakage Involves PECAM1 Phosphorylation¹

Laboratory of Tumor Immunology, Scientific Institute San Raffaele, Via Olgettina 60, I-20132 Milan [E. F., E. T., M. R. Z.], Department of Pharmacology, Consiglio Nazionale delle Ricerche Cytopharmacology and B. Ceccarelli Centers [A. V.] and Department of Pathology [M. E. F.], University of Milan, 20100 Milan, Italy Department of Molecular Cardiobiology, Boyer Center for Molecular Medicine and the Raymond and Beverly Sackler Cardiobiology Laboratory, Yale University School of Medicine, New Haven, Connecticut [J. R. B.]; Department of Internal Medicine, University of Milan, 20132 Milan [R. P.], and Human Immunology Unit, Scientific Institute San Raffaele-Dibit, 20132 Milan [R. P.]

Herein we show that exposure of human umbilical vein endothelial cells to tumor necrosis factor (TNF) 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 TNF-dependent vascular leakage in mouse liver. We propose that the involvement of PECAM1 in TNF-mediated effects on vascular permeability may depend on a dynamically regulated cytoskeletal association, related to the degree of PECAM1 phosphorylation.

¹ This work was partially supported by the Italian Association for Cancer Research (AIRC 1995/96), the National Research Council (CNR 95.10969.CT04 and P.F.ACRO 96), and by NIH grant HL43331. J.R.B. is a Raymond and Beverly Sackler Foundation, Inc. Scholar.

² To whom requests for reprints should be addressed. Phone: 39 2 2643 2612; Fax: 39 2 2643 2482; E-mail: zocchim@hsr.it.

Received 4/15/96. Accepted 5/30/96.

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