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Tumor necrosis factor and interleukin-1 induce expression of the verocytotoxin receptor globotriaosylceramide on human endothelial cells: Implications for the pathogenesis of the hemolytic uremic syndrome


Author: Kar, N.C.A.J. van de · Monnens, L.A.H. · Karmali, M.A. · Hinsbergh, V.W.M. van
Institution: Instituut voor verouderings- en vaatziekten onderzoek TNO
Source:Blood, 11, 80, 2755-2764
Identifier: 231743
Keywords: Health · cell surface receptor · cycloheximide · globotriaosylceramide · interleukin 6 · lipopolysaccharide · lymphotoxin · recombinant interleukin 1 · recombinant interleukin 1alpha · recombinant interleukin 1beta · recombinant tumor necrosis factor alpha · thrombin · verotoxin · article · concentration response · controlled study · cytopathogenic effect · cytotoxicity · endothelium cell · enzyme induction · escherichia coli · hemolytic uremic syndrome · human · human cell · pathogenesis · priority journal · protein synthesis inhibition · receptor binding · thin layer chromatography · Bacterial Toxins · Carbohydrate Conformation · Carbohydrate Sequence · Cell Survival · Cells, Cultured · Cycloheximide · Endothelium, Vascular · Glycolipids · Hemolytic-Uremic Syndrome · Human · Interleukin-1 · Kinetics · Lipopolysaccharides · Molecular Sequence Data · Receptors, Cell Surface · Shiga-Like Toxin I · Support, Non-U.S. Gov't · Time Factors · Trihexosylceramides · Tumor Necrosis Factor · Umbilical Veins


The epidemic form of the hemolytic uremic syndrome (HUS), beginning with an acute gastroenteritis, has been associated with a verocytotoxin-producing Escherichia coli infection. The endothelial cell is believed to play an important role in the pathogenesis of HUS. Endothelial cell damage by verocytotoxin-1 (VT-1) in vitro is potentiated by the additional exposure of inflammatory mediators, such as tumor necrosis factor-α (TNF-α). Preincubation of human umbilical vein endothelial cells (HUVEC) with TNF-α resulted in a 10- to 100-fold increase of specific binding sites for 125I- VT-1. Furthermore, interleukin-1 (IL-1), lymphotoxin (TNF-β), and lipopolysaccharide (LPS) also markedly increase VT-1 binding. Several hours' exposure to TNF-α was enough to enhance the number of VT-1 receptors on the endothelial cells for 2 days. The TNF-α-induced increase in VT-1 binding could be inhibited by simultaneous addition of the protein synthesis inhibitor cycloheximide. Glycolipid extracts of TNF-α-treated cells tested on thin-layer chromatography demonstrated an increase of globotriaosylceramide (GbOse3cer), a functional receptor for VT-1, which suggests that preincubation of human endothelial cells with TNF-α leads to an increase in GbOse3cer synthesis in these cells. We conclude from this study that TNF-α and IL-1 induce one (or more) enzyme(s) that is (are) rate- limiting in the synthesis of the glycolipid VT-1 receptor, GbOse3cer. These in vitro studies suggest that, in addition to VT-1, inflammatory mediators play an important role in the pathogenesis of HUS. Chemicals/CAS: cycloheximide, 642-81-9, 66-81-9; globotriaosylceramide, 71965-57-6; thrombin, 9002-04-4; verotoxin, 108066-86-0; Bacterial Toxins; Cycloheximide, 66-81-9; globotriaosylceramide, 71965-57-6; Glycolipids; Interleukin-1; Lipopolysaccharides; Receptors, Cell Surface; Shiga-Like Toxin I; Shiga-like toxin receptor; Trihexosylceramides; Tumor Necrosis Factor