Endogenously produced urokinase amplifies tumor necrosis factor‐α secretion by THP‐1 mononuclear phagocytes

Abstract

This study examined the effects of endogenous urokinase (uPA) on lipopolysaccharide (LPS)‐stimulated tumor necrosis factor α (TNF‐α) secretion in THP‐1 mononuclear phagocytes. Anti‐uPA monoclonal antibody (mAb) suppressed LPS‐driven TNF‐α secretion by 61.6 ± 5.9% (P < .001), and PAI‐1, a uPA inhibitor, suppressed it to 53.1 ± 8.2% of the control value (P < .001). Up‐regulation of TNF‐α mRNA was suppressed in parallel with secreted TNF‐α protein. TNF‐α secretion was unaffected by depleting plasminogen or by aprotinin, a plasmin inhibitor. When endogenous uPA was displaced from the cell, exogenous high‐molecular‐weight (intact) uPA augmented LPS‐driven TNF‐α secretion. By contrast, a uPA fragment containing the catalytic domain was inhibitory, and the uPA receptor‐binding domain had no effect. We conclude that endogenous uPA amplifies TNF‐α neosynthesis of UPS‐stimulated THP‐1 mononuclear phagocytes. The effect requires intact uPA and is independent of plasmin activity. This represents a novel mechanism by which a mononuclear phagocyte–derived protease contributes to generating proinflammatory signals.