STAUROSPORINE BLOCKS DOWN-REGULATION OF MONOCYTE-ASSOCIATED TISSUE FACTOR

Inflammatory agents including bacterial endotoxin (LPS) and low concentrations of phorbol myristate acetate (PMA) stimulate human peripheral blood monocytes to transiently express tissue factor procoagulant activity. Concentrations of PMA that cause the cytosol-to-membrane translocation of protein kinase C (PKC) (10(-9)-10(-7) M) induce a rapid decrease in monocyte tissue factor activity. Staurosporine, an inhibitor of protein kinase C, enhances the stimulatory effect of low concentrations of PMA on monocyte expression of tissue factor activity and blocks suppression of tissue factor activity at high PMA concentrations. Furthermore, staurosporine prolongs LPS-induced tissue factor expression in monocytes. These results suggest that protein kinases modulate tissue factor activity in human monocytes by regulating both induction and down-regulation.