Tumor Necrosis Factor Alpha Increases Human Cerebral Endothelial Cell Gb ₃ 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-α) upregulates Gb3 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 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

p38 Mitogen-Activated Protein Kinase Mediates Lipopolysaccharide and Tumor Necrosis Factor Alpha Induction of Shiga Toxin 2 Sensitivity in Human Umbilical Vein Endothelial Cells

“…These cells include human glomerular endothelial cells, glomerular visceral epithelial cells (podocytes), proximal tubule cells, and mesangial cells (22,65). Gb 3 levels are increased on brain microvascular endothelial cells (15) after treatment with tumor necrosis factor alpha (TNF-␣), providing a rationale for Stx-induced brain injury (51). Finally, Gb 3 can be induced on human umbilical vein endothelial cells (HUVEC) with lipopolysaccharide (LPS), TNF-␣, or interleukin-1␤ (IL-1␤) and has been widely used as an in vitro model for endothelial damage by Stx (27, 29, 37-39, 60, 68).…”

Shiga Toxin 2 and Lipopolysaccharide Induce Human Microvascular Endothelial Cells To Release Chemokines and Factors That Stimulate Platelet Function

“…Gb3/CD77 is present on the surfaces of different cell types including human glomerular endothelial cells, glomerular epithelial cells (35), and brain microvascular endothelial cells (19). Renal microvascular endothelial cells constitutively express 50 times more Stx receptor and are more sensitive to the toxic effects of Shiga toxins than human umbilical vein endothelial cells (HUVEC) (61).…”

Human microvascular endothelial cells resist Shiga toxins by IFN-γ treatment in vitro

“…To date, many in vitro studies have indicated that proinflammatory cytokines are intimately involved in the endothelial damage caused by Stxs, through enhancing receptor expression and sensitizing the target cells (Molostvov et al, 2001;Eisenhauer et al, 2001). In the particular case of native HLMECs, which exhibit high sensitivity to Stxs in the basal state like other microvascular endothelial cells (Ohmi et al, 1998;Pijpers et al, 2001), the CD 50 decreased only moderately even after 4 days treatment with a high TNF-a dose (Table 1) and not at all after 1 day of treatment (data not shown).…”

“…Stxs are believed to damage endothelial cells of the microvascular system especially in the kidney, lung and colon epithelium (Laurence & Mitra, 1997). The endothelial cells express the specific receptor for Stxs, globotriaosyl ceramide (Gb3), and its content is enhanced by various proinflammatory cytokines, such as TNF-a (Molostvov et al, 2001;Eisenhauer et al, 2001). After endocytosis, Stxs travel through the Golgi apparatus (Arab & Lingwood, 1998), are processed by furin (Garred et al, 1995) and then, finally, reach their cellular target, the 60S ribosome.…”