Urokinase and type I plasminogen activator inhibitor production by normal human hepatocytes: modulation by inflammatory agents.
We examined the effects of inflammatory cytokines (interleukin-1 beta, tumor necrosis factor-alpha and transforming growth factor-beta) on the plasminogen activator system (urokinase, tissue-type plasminogen activator, type 1 plasminogen activator inhibitor) in primary cultures of human hepatocytes. We show that interleukin-1 beta and tumor necrosis factor-alpha increase urokinase-type plasminogen activator production, reinforcing the concept that increased urokinase production is associated with inflammatory processes. By contrast, the same agents (i.e., interleukin-1 beta and tumor necrosis factor-alpha) do not stimulate plasminogen activator inhibitor type 1 production. This latter observation rules out hepatocytes as a major cellular source of plasmatic plasminogen activator inhibitor type 1 during acute-phase-related responses. Among the inflammatory agents used, transforming growth factor-beta was found to be the most effective modulator of both urokinase-type plasminogen activator and plasminogen activator inhibitor type 1, inducing severalfold increases of activity of urokinase-type plasminogen activator, antigen and the corresponding mRNA and increasing plasminogen activator inhibitor type 1 antigen and mRNA levels. Urokinase-type plasminogen activator and plasminogen activator inhibitor type 1 modulation by transforming growth factor-beta may play a critical role in hepatic pathophysiology.
Laboratories GLAXO, Centre de Recherches, Les Ulis, France.
N
N
Busso
E
E
Nicodeme
C
C
Chesne
A
A
Guillouzo
D
D
Belin
F
F
Hyafil
D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D007375:Interleukin-1 / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D010959:Tissue Plasminogen Activator / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000096:biosynthesis* / Q000235:genetics
D016207:Cytokines; D007375:Interleukin-1; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator