Tumor necrosis factor and interleukin 1 induce expression of the glycolipid verotoxin receptor in human endothelial cells. Implications for the pathogenesis of the haemolytic uraemic syndrome.

Activation of the endothelium by TNF or IL-1 results in altered haemostatic properties of and leukocyte binding to the endothelium. In haemolytic uraemic syndrome, the endothelium of the kidney and sometimes other tissues is severely damaged, presumably by a bacterial toxin, verotoxin (VT). In vitro studies have demonstrated that endothelial cells become sensitive to this toxin when they are exposed to TNF alpha or IL-1, inflammatory mediators which are produced by monocytes and mesangial cells and which may play a role in the kidney. In this report we demonstrate the influence of inflammatory mediators on the binding of VT to endothelial cells. Preincubation of human endothelial cells with TNF alpha for 24 h resulted in a ten- to hundred-fold increase of specific binding sites for 125I-VT-1. IL-1 and lymphotoxin (TNF beta) also markedly increased VT-1 binding. An exposure of only 6 h to TNF alpha was already enough to enhance the number of VT-1 binding sites on endothelial cells for at least 2 days. In order to demonstrate that the increases in VT binding was due to an increase in the functional VT receptor, glycolipid extracts of TNF alpha-treated cells were analyzed by thin layer chromatography. An increase of globotriaosylceramide (Gb3) was observed, suggesting that that preincubation of endothelial cells with TNF alpha leads to an increase in Gb3 synthesis in these cells. Inhibition of protein synthesis by cycloheximide prevented the increase in VT receptors induced by TNF alpha.(ABSTRACT TRUNCATED AT 250 WORDS)