SYNERGISTIC INDUCTION OF ENDOTHELIAL TISSUE FACTOR BY TUMOR-NECROSIS-FACTOR AND VASCULAR ENDOTHELIAL GROWTH-FACTOR - FUNCTIONAL-ANALYSIS OFTHE TUMOR-NECROSIS-FACTOR RECEPTORS

Tissue factor expression on the surface of endothelial cells can be in duced by tumor necrosis factor (TNF) and vascular endothelial growth f actor (VEGF) in a synergistic manner, We have investigated the role of the two different TNF receptors for this synergy, Firstly, stimulatio n of the 60 kDa TNF receptor (TNFR60) by a mutant of TNF specific for TNFR60 induced responses comparable to wild-type TNF. In contrast, sti mulation of TNFR80 by a TNFR80-specific TNF mutein did not result in e nhancement of tissue factor expression even in the presence of a subop timal TNFR60 triggering, Secondly, we tested neutralizing TNF receptor antibodies for inhibition of tissue factor synthesis induced by VEGF and TNF. A TNFR60-specific antibody inhibited tissue factor production over a broad range of TNF concentrations, indicating an essential rol e of TNFR60 in the TNF/VEGF synergy, In contrast, blocking of TNF bind ing to TNFR80 strongly inhibited TNF-induced tissue factor expression at low, but less pronounced at high, TNF concentrations, In conclusion , these data are in agreement with a model in which TNFR80 participate s in the synergy between VEGF and low concentrations of soluble TNF by passing the ligand to the signalling TNFR60.