INDUCTION OF ENDOTHELIAL-CELL SURFACE MOLECULES BY TUMOR-NECROSIS-FACTOR IS BLOCKED BY PROTEIN-TYROSINE-PHOSPHATASE INHIBITORS - ROLE OF THE NUCLEAR TRANSCRIPTION FACTOR NF-CHI-B

Recent studies from our laboratory have indicated that protein tyrosin e phosphatase (PTPase) inhibitors can down-modulate the tumor necrosis factor (TNF)-mediated activation of the nuclear transcription factor NF-kappa B in ML-1a, a monocytic cell line (Singh and Aggarwall J. Bio l. Chem. 1995: 270: 10631). Since TNF is one of the major inducers of various adhesion molecules in human endothelial cells and their expres sion is known to require the activation of NF-kappa B, we examined the effect of PTPase inhibitors on the TNF-mediated induction of intracel lular adhesion molecule (ICAM)-1. vascular cell adhesion molecule (VCA M)-1 and endothelial leukocyte adhesion molecule (ELAM)-1. Like ML-1a, human dermal microvessel endothelial cells (MVEC) treated with TNF ra pidly activated (within 30 min) NF-kappa B; this effect was completely abolished by co-treatment with phenylarsine oxide (PAO), a specific i nhibitor of PTPase. The induction of ICAM-1, VCAM-1, and ELAM-1 by TNF in MVEC occurred within 6 h and was also completely down-regulated by PAO in a dose-dependent manner. PAO was found to be effective even wh en added 3 h after TNF, suggesting a rapid mode of action of this inhi bitor. Besides PAO, other inhibitors of PTPase, including pervanadate and diamide, also blocked TNF-dependent NF-kappa B activation and indu ction of all the three adhesion proteins. Consistent with these result s, the attachment of monocytes to MVEC was also blocked by the PTPase inhibitors. Thus. overall, our results demonstrate that a PTPase is in iolved either directly or indirectly in the pathway leading to the in duction of endothelial cell adhesion molecules by TNF, Because of thei r role in cell adhesion, PTPase may provide a novel target of drug dev elopment for treatment of inflammation, atherogenesis, and tumor metas tasis.