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

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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.

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