INDUCTION OF TISSUE FACTOR ON MONOCYTES BY ADHESION TO ENDOTHELIAL-CELLS

Activated monocytes express tissue factor (TF), a protein that is impo rtant in the pathogenesis of thrombotic disorders. We sought to charac terize an adhesion-dependent pathway for monocyte activation. In this study, we showed that adhesion of monocytes to cytokine-activated endo thelial cells (EC) increased (similar to 5- to 10-fold) monocyte proco agulant activity (PCA). The PCA was attributed to TF because it was de pendent on the coagulation factors VII and X, but not VIII, and was co mpletely blocked by an anti-TF mAb. Direct cell-cell contact between m onocytes and EC was required. The induction of TF was rapid, peaked at 30 min, and persisted for 4 h. Northern analysis revealed a rapid (si milar to 30 min) increase in TF mRNA following adhesion, distinct from that induced by LPS (similar to 2-4 h). Four-hour TNF-treated EC supp orted TF expression, but 0.5- and 24-h TNF-treated EC had no effect. A n anti-E-selectin mAb (H18/7) exerted partial inhibition, whereas anti -VCAM-1, ICAM-1, and CD11/CD18 mAbs had no inhibition. Synthetic Lewis X (Le(x)) oligosaccharide partially blocked TF induction, whereas sia lyl-Le(x) (sLe(x)) oligosaccharide had no effect. Cross-linking Le(x) on monocytes, but not sLe(x), significantly increased (similar to-10-f old) the TF expression. Le(x) cross-linking induced TF in 30 min and l asted for 4 h. All seventeen anti-Le(x) mAbs induced significant amoun t of TF generation, and epitope mapping revealed a single binding epit ope on Le(x). These findings indicate that adhesion of monocytes to ac tivated EC induces TF generation, and also suggest that Le(x) may repr esent an important signaling molecule on monocytes.