title: 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.
abstract: 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-alpha (TNF-alpha). Preincubation of human umbilical vein endothelial cells (HUVEC) with TNF-alpha resulted in a 10- to 100-fold increase of specific binding sites for 125I-VT-1. Furthermore, interleukin-1 (IL-1), lymphotoxin (TNF-beta), and lipopolysaccharide (LPS) also markedly increase VT-1 binding. Several hours' exposure to TNF-alpha was enough to enhance the number of VT-1 receptors on the endothelial cells for 2 days. The TNF-alpha-induced increase in VT-1 binding could be inhibited by simultaneous addition of the protein synthesis inhibitor cycloheximide. Glycolipid extracts of TNF-alpha-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-alpha leads to an increase in GbOse3cer synthesis in these cells. We conclude from this study that TNF-alpha 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.
authors.affiliation: Gaubius Laboratory, IVVO-TNO, Leiden, The Netherlands.
authors.forename: N C
authors.initials: NC
authors.lastname: van de Kar
authors.forename: L A
authors.initials: LA
authors.lastname: Monnens
authors.forename: M A
authors.initials: MA
authors.lastname: Karmali
authors.forename: V W
authors.initials: VW
authors.lastname: van Hinsbergh
mesh_terms: D001427:Bacterial Toxins / Q000378:metabolism / Q000494:pharmacology*; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006017:Glycolipids / Q000096:biosynthesis* / Q000302:isolation & purification / Q000378:metabolism; D006463:Hemolytic-Uremic Syndrome / Q000503:physiopathology*; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology*; D007700:Kinetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008969:Molecular Sequence Data; D011956:Receptors, Cell Surface / Q000096:biosynthesis* / Q000378:metabolism; D022622:Shiga Toxin 1; D013997:Time Factors; D014281:Trihexosylceramides / Q000096:biosynthesis* / Q000737:chemistry / Q000302:isolation & purification; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014471:Umbilical Veins
chemical_list: D001427:Bacterial Toxins; D006017:Glycolipids; D007375:Interleukin-1; D008070:Lipopolysaccharides; D011956:Receptors, Cell Surface; D022622:Shiga Toxin 1; C068556:Shiga-like toxin receptor; D014281:Trihexosylceramides; D014409:Tumor Necrosis Factor-alpha; C018549:globotriaosylceramide; D003513:Cycloheximide