Tumor Necrosis Factor Induces the Production of Urokinase-Type Plasminogen Activator by Human Endothelial Cells

• Published in: Blood 1990-05, Vol.75 (10), p.1991-1998
• Main Authors: van Hinsbergh, Victor W.M., van den Berg, Eva A., Fiers, Walter, Dooijewaard, Gerard
• Format: Article
• Language: English
• Subjects: Analysis of the immune response. Humoral and cellular immunity; Biological and medical sciences; Biological Factors - pharmacology; Cells, Cultured; Cytokines; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Fibrinolysin - pharmacology; Fibrinolytic Agents - metabolism; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Expression Regulation - drug effects; Humans; Immunobiology; Lymphokines, interleukins ( function, expression); Plasminogen Activators - genetics; Plasminogen Activators - metabolism; Plasminogen Activators - physiology; Plasminogen Inactivators - metabolism; Regulatory factors and their cellular receptors; RNA, Messenger - genetics; RNA, Messenger - metabolism; Tumor Necrosis Factor-alpha - pharmacology; Urokinase-Type Plasminogen Activator - genetics; Urokinase-Type Plasminogen Activator - metabolism; Urokinase-Type Plasminogen Activator - physiology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V75.10.1991.1991

Endothelial cells play an important role in the regulation of fibrinolysis by the production of several key regulatory proteins. The cytokines tumor necrosis factor (TNF), lym-photoxin. and interleukin-1 (IL-1), but not interleukin-6, increase the production of plasminogen activator inhibitor-1 (PAI-1) by endothelial cells, whereas they have no stimulatory effect on the production of tissue-type plasminogen activator (t-PA). Primary cultures of human endothelial cells release very little urokinase-type plasminogen activator (u-PA). We report here that TNF and lymphotoxin induce, in a concentration-dependent way, the production of both cellular and secreted u-PA antigen in primary and subcultured human endothelial cells. The TNF-induced increase was accompanied by a more than 10-fold increase in u-PA mRNA. Upon stimulation of early passage umbilical vein endothelial cells by TNF, u-PA was predominantly secreted at the basolateral side, whereas PAI activity and t-PA were found in more equal amounts at the apical and basolateral sides of the cell monolayers. TNF-stimulated u-PA secretion by subcultured human aorta endothelial cells showed only a marginal polarity. The u-PA antigen was present in a plasmin-activatable form (single chain u-PA) and in a nonactivatable form (probably u-PA: PAI-1 complex). During the induction of u-PA by TNF, the ratio between plasmin-activatable u-PA and total u-PA decreased markedly. This may indicate that TNF also increases the degree of u-PA activation. The parallel induction of the synthesis and secretion of both u-PA and PAI-1 by endothelial cells adds a new aspect to the alterations of the fibrinolytic system caused by inflammatory mediators. This aspect may be significant for the regulation of cell-associated and interstitial plasminogen activator activity.