Endogenously produced urokinase amplifies tumor necrosis factor-alpha secretion by THP-1 mononuclear phagocytes.
This study examined the effects of endogenous urokinase (uPA) on lipopolysaccharide (LPS)-stimulated tumor necrosis factor alpha (TNF-alpha) secretion in THP-1 mononuclear phagocytes. Anti-uPA monoclonal antibody (mAb) suppressed LPS-driven TNF-alpha 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-alpha mRNA was suppressed in parallel with secreted TNF-alpha protein. TNF-alpha 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-alpha 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-alpha neosynthesis of LPS-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.
Sitrin
R G
RG
Department of Internal Medicine, University of Michigan, Ann Arbor 48109-0360, USA.
Shollenberger
S B
SB
Strieter
R M
RM
Gyetko
M R
MR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D005341:Fibrinolysin / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007951:Leukemia, Myeloid; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D010586:Phagocytes / Q000378:metabolism*; D010958:Plasminogen / Q000378:metabolism; D010960:Plasminogen Activators / Q000494:pharmacology; D013268:Stimulation, Chemical; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism*; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis / Q000276:immunology / Q000502:physiology*
D000911:Antibodies, Monoclonal; D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D010958:Plasminogen; D010960:Plasminogen Activators; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator