Tumor Necrosis Factor Alpha Increases Human Cerebral Endothelial Cell Gb 3 and Sensitivity to Shiga Toxin

Abstract

ABSTRACT Hemolytic uremic syndrome (HUS) is associated with intestinal infection by enterohemorrhagic Escherichia coli strains that produce Shiga toxins. Globotriaosylceramide (Gb 3 ) is the functional receptor for Shiga toxin, and tumor necrosis factor alpha (TNF-α) upregulates Gb 3 in both human macrovascular umbilical vein endothelial cells and human microvascular brain endothelial cells. TNF-α treatment enhanced Shiga toxin binding and sensitivity to toxin. This upregulation was specific for Gb 3 species containing normal fatty acids (NFA). Central nervous system (CNS) pathology in HUS could involve cytokine-stimulated elevation of endothelial NFA-Gb 3 levels. Differential expression of Gb 3 species may be a critical determinant of Shiga toxin toxicity and of CNS involvement in HUS.