Highly charged polyanionic ligands of the scavenger receptor trigger macrophage secretion of urokinase-type plasminogen activator (uPA). In experiments reported here, we have investigated the intracellular and extracellular regulation of polyanion-induced macrophage plasminogen activation. Exposure of a macrophage cell line (RAW264.7) to either fucoidan or phorbol myristate acetate (PMA) stimulates the secretion of uPA, whereas calcium ionophore or dibutyryl cyclic AMP had no effect. Moreover, preincubation of macrophages with inhibitors of protein kinase C reduced (50-60%) the ability of both fucoidan and PMA to trigger the secretion of uPA, whereas aspirin and eicosatetraenoic acid had no effect. Both PMA and fucoidan treatment of RAW264.7 cells resulted in a rapid and transient increase in the steady state levels of uPA mRNA. However, in marked contrast to that observed with PMA, fucoidan-induced expression of RAW264.7 uPA activity was partially insensitive to cycloheximide and actinomycin D. In addition, fucoidan-induced uPA activity was detected in conditioned media in as little as 15 min, whereas PMA-induced uPA activity did not increase until 2 h. In addition to stimulating macrophage secretion of uPA, fucoidan bound uPA and had a small stimulatory affect on uPA activity. The binding does not interfere with the catalytic site on the B chain, or require the receptor binding or kringle domains on the A chain.