Print Email Facebook Twitter Tumor necrosis factor increases the production of plasminogen activator inhibitor in human endothelial cells in vitro and in rats in vivo Title Tumor necrosis factor increases the production of plasminogen activator inhibitor in human endothelial cells in vitro and in rats in vivo Author van Hinsbergh, V.W.M. Kooistra, T. van den Berg, E.A. Princen, H.M.G. Fiers, W. Emeis, J.J. Gaubius instituut TNO Publication year 1988 Abstract The vascular endothelium plays an important role in fibrinolysis by producing tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor (PAI). The monokine tumor necrosis factor (human recombinant TNF) increased the production of PAI by cultured human endothelial cells from umbilical vein (twofold) and from foreskin microvessels (four to eight fold). This was demonstrated by titration of endothelial cell-conditioned medium with t-PA, by reverse fibrin autography, and by immunoprecipitation of [35S]PAI-1 by anti-PAI-1 IgG. TNF also induced a marked increase in PAI-1 messenger RNA (mRNA) in the cells. The stimulation of PAI activity by TNF was seen at 4 U/mL and reached a maximum at 500 U/mL. Human recombinant lymphotoxin and interleukin-1 (α and β) also stimulated the production of PAI activity, while interleukin-6 was ineffective. Separate additions of TNF or interleukin-1 (IL-1) at optimal concentrations (500 U/mL and 5 U/mL, respectively) resulted in a comparable stimulation of PAI production by endothelial cells. The simultaneous addition of both mediators resulted in an additive effect. The effect of TNF could not be prevented by the addition of polymyxin B or by anti-IL-1 antibodies. Therefore, it is unlikely that TNF acts through the induction of IL-1 secretion by endothelial cells. Two hours after a bolus injection of 250,000 U/kg TNF into rats, a fivefold increase in circulating PAI levels was found. In the next ten hours, the levels returned to normal. Blood platelets do not significantly contribute to the increase in circulating PAI, because the number of platelets did not change after TNF injection and the amount of PAI in blood platelets is not sufficient for several hours during an increase in PAI activity. The acute phase reactants, fibrinogen and α2-antiplasmin in rat plasma, were altered little if any two to 24 hours after injection of 250,000 U/kg TNF. In vitro, TNF did not change PAI production by human and rat hepatocytes in primary monolayer culture. Therefore, it is most likely that vascular endothelial cells contribute to the increased amount of circulating PAI induced by TNF in vivo. This increase in PAI activity might decrease fibrinolysis. Chemicals/CAS: plasminogen activator inhibitor, 105844-41-5; Glycoproteins; Lymphotoxin; Plasminogen Inactivators; RNA, Messenger; Tissue Plasminogen Activator, EC 184.108.40.206; Tumor Necrosis Factor Subject Interleukin 1Interleukin 6LymphotoxinPlasminogen activator inhibitorRadioisotopeTumor necrosis factorAnimal experimentAnimal modelCell cultureEndothelium cellHumanHuman cellIntravenous drug administrationLiver cellNonhumanAnimalBlotting, NorthernCells, CulturedEndothelium, VascularGene Expression RegulationGlycoproteinsIn VitroLymphotoxinMalePlasminogen InactivatorsRatsRats, Inbred StrainsRNA, MessengerSupport, Non-U.S. Gov'tTissue Plasminogen ActivatorTumor Necrosis Factor To reference this document use: http://resolver.tudelft.nl/uuid:db9c1fb9-8f4b-42a7-acd6-c45fc811f0b0 TNO identifier 230519 ISSN 0006-4971 Source Blood, 72 (5), 1467-1473 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.