Abstract
This study addresses the basis for regional microvascular susceptibility to bacterial toxins implicated in hemolytic uremic syndrome. The results indicate a relationship between the degree of Shiga toxin sensitivity of human endothelial cells from different sources and the amount of globotriaosylceramide (Gb3) glycosphingolipid receptor for Shiga toxin expressed by these cells. Cell viability and protein synthesis of renal endothelial cells were reduced to 50% by 1 pM Shiga toxin, while umbilical vein cells were not affected by > 1 nM toxin. Similarly, basal levels of Gb3 were approximately 50 times higher in renal endothelial cells than in the umbilical endothelial cells. Pre-exposure of umbilical endothelial cells to tumor necrosis factor-alpha or bacterial lipopolysaccharide increased Gb3 content 4-6-fold coincident with increases in sensitivity to cytotoxic and protein synthesis inhibitory effects of Shiga toxin. Lipopolysaccharide induction of both Gb3 and sensitivity to Shiga toxin cytotoxic action in umbilical endothelial cells was dependent on the structure of lipopolysaccharide. Neither tumor necrosis factor-alpha nor lipopolysaccharide altered the Shiga toxin sensitivity or the Gb3 content of renal endothelial cells. These data indicate that differential endothelial expression of glycolipid receptors for Shiga toxins may be responsible for localized involvement of the kidney in hemolytic uremic syndrome.
Highlights
This study addresses the basis for regional microvbaiosl-ogically active proteins [2, 4,5,6].Gb, is known as cular susceptibility to bacterial toxins implicatedin hemolytic uremic syndrome
Threesults indicate a relationship between the degree of Shigtoaxin sensitivity of human endothelial cells from different sources and the amount of globotriaosylceramide (Gb,g) lycosphingolipidreceptor for Shigatoxinexpressedby these cells
Escherichia coli LPS was the most active, followed by diphosphoryl lipid A, Pseudomonas LPS, and monophosphoryl lipid A (Fig. 5 ). These results indicate a correlation between induction of Gb, expression and an increased sensitivity of Human umbilical vein endothelial cells (HUVEC) to Shiga rated on a normal phase silica high performance liquid chromatog- toxin
Summary
(Received for publication, November 12, 1992, and in revised form, March 16, 1993). Tom G. We have examined the expression of in sensitivity to cytotoxic and proteinsynthesis inhib- glycosphingolipidsby human vascular endothelial cells. Lipopolysaccharide induc- cells are theputative targetof Shiga toxin in bacterial disease tion of botGhb and sensitivity to Shigatoxin cytotoxic of humans [8, 9]. Shigatoxin sensitivity or the Gba contentofrenal expressing Gb, are sensitive to Shiga toxin and bind and endothelial cells. These data indicate thatdifferential internalize the toxin. The a-subunitis endothelial toxins may the kidney bienexphrreeesmpssooinloynostifibcgleluycrfooermlipilcoidcsaylrinezdceedrpotimnovreso. lvfeomr eSnht igopsaafir-nosguclbeesusnneuidtcilbneyaoctaitdivterayitnpess2in8-6Sl0ikrReSNcrleAiba,ovysaoigemeld.eiTsnhgbeyri“bdaocestpoivumaritenesdait”nioc2an7p-oakfbDlaea of carrying out peptide elongation [10,11,12]
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