title: Tumor necrosis factor alpha increases human cerebral endothelial cell Gb3 and sensitivity to Shiga toxin.
abstract: Hemolytic uremic syndrome (HUS) is associated with intestinal infection by enterohemorrhagic Escherichia coli strains that produce Shiga toxins. Globotriaosylceramide (Gb3) is the functional receptor for Shiga toxin, and tumor necrosis factor alpha (TNF-alpha) upregulates Gb3 in both human macrovascular umbilical vein endothelial cells and human microvascular brain endothelial cells. TNF-alpha treatment enhanced Shiga toxin binding and sensitivity to toxin. This upregulation was specific for Gb3 species containing normal fatty acids (NFA). Central nervous system (CNS) pathology in HUS could involve cytokine-stimulated elevation of endothelial NFA-Gb3 levels. Differential expression of Gb3 species may be a critical determinant of Shiga toxin toxicity and of CNS involvement in HUS.
authors.affiliation: Bedford VA Medical Center, Bedford, and Boston University, Boston, Massachusetts, USA.
authors.forename: P B
authors.initials: PB
authors.lastname: Eisenhauer
authors.forename: P
authors.initials: P
authors.lastname: Chaturvedi
authors.forename: R E
authors.initials: RE
authors.lastname: Fine
authors.forename: A J
authors.initials: AJ
authors.lastname: Ritchie
authors.forename: J S
authors.initials: JS
authors.lastname: Pober
authors.forename: T G
authors.initials: TG
authors.lastname: Cleary
authors.forename: D S
authors.initials: DS
authors.lastname: Newburg
mesh_terms: D001812:Blood-Brain Barrier / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000187:drug effects*; D006801:Humans; D022621:Shiga Toxin / Q000494:pharmacology*; D014281:Trihexosylceramides / Q000096:biosynthesis*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
chemical_list: D014281:Trihexosylceramides; D014409:Tumor Necrosis Factor-alpha; C018549:globotriaosylceramide; D022621:Shiga Toxin