title: Tumor necrosis factor induces the production of urokinase-type plasminogen activator by human endothelial cells.
abstract: 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), lymphotoxin, 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.
authors: Gaubius Institute TNO, Leiden, The Netherlands.
authors: V W
authors: VW
authors: van Hinsbergh
authors: E A
authors: EA
authors: van den Berg
authors: W
authors: W
authors: Fiers
authors: G
authors: G
authors: Dooijewaard
mesh_terms: D001685:Biological Factors / Q000494:pharmacology; D002478:Cells, Cultured; D016207:Cytokines; D004730:Endothelium, Vascular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005341:Fibrinolysin / Q000494:pharmacology; D005343:Fibrinolytic Agents / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D010960:Plasminogen Activators / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015849:Plasminogen Inactivators / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism* / Q000502:physiology
chemical_list: D001685:Biological Factors; D016207:Cytokines; D005343:Fibrinolytic Agents; D015849:Plasminogen Inactivators; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D010960:Plasminogen Activators; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator