Cytotoxic effect of Shiga toxin-2 holotoxin and its B subunit on human renal tubular epithelial cells

Creydt, Virginia Pistone; Silberstein, Claudia; Zotta, Elsa; Ibarra, Cristina

doi:10.1016/j.micinf.2005.07.005

Cited by 57 publications

(63 citation statements)

References 32 publications

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“…These inflammatory mediators have been shown to increase Gb 3 and/or Stx sensitivity in kidney cell types such as mesangium (53), tubular epithelial cells (10), and glomerular microvascular endothelial cells even though TNF-␣ does not affect the retrograde transport of the Stx B subunit in these cells (65). We also show that these cells required minimal times of exposure to LPS or TNF-␣ in order to have increased sensitivity to Stx2.…”

Section: Discussionmentioning

confidence: 62%

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

et al. 2008

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Escherichia coli O157:H7 Shiga toxin 2 (Stx2), one of the causative agents of hemolytic-uremic syndrome, is toxic to endothelial cells, including primary cultured human umbilical vein endothelial cells (HUVEC). This sensitivity of cells to Stx2 can be increased with either lipopolysaccharide (LPS) or tumor necrosis factor alpha (TNF-␣). The goal of the present study was to identify the intracellular signaling pathway(s) by which LPS and TNF-␣ sensitize HUVEC to the cytotoxic effects of Stx2. To identify these pathways, specific pharmacological inhibitors and small interfering RNAs were tested with cell viability endpoints. A time course and dose response experiment for HUVEC exposure to LPS and TNF-␣ showed that a relatively short exposure to either agonist was sufficient to sensitize the cells to Stx2 and that both agonists stimulated intracellular signaling pathways within a short time. Cell viability assays indicated that the p38 mitogen-activated protein kinase (MAPK) inhibitors SB202190 and SB203580 and the general protein synthesis inhibitor cycloheximide inhibited both the LPS and TNF-␣ sensitization of HUVEC to Stx2, while all other inhibitors tested did not inhibit this sensitization. Additionally, SB202190 reduced the cellular globotriaosylceramide content under LPS-and TNF-␣-induced conditions. In conclusion, our results show that LPS and TNF-␣ induction of Stx2 sensitivity in HUVEC is mediated through a pathway that includes p38 MAPK. These results indicate that inhibition of p38 MAPK in endothelial cells may protect a host from the deleterious effects of Stx2.

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Section: Discussionmentioning

confidence: 62%

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

et al. 2008

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“…4). In contrast, apoptosis was observed previously when experiments were performed using transformed cells (4,17,20) or primary cells obtained from renal carcinoma patients (6,53). The role of apoptosis in Stx-mediated disease is also unclear.…”

Section: Discussionmentioning

confidence: 80%

Shiga Toxin Subtypes Display Dramatic Differences in Potency

et al. 2011

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Purified Shiga toxin (Stx) alone is capable of producing systemic complications, including hemolytic-uremic syndrome (HUS), in animal models of disease. Stx includes two major antigenic forms (Stx1 and Stx2), with minor variants of Stx2 (Stx2a to -h). Stx2a is more potent than Stx1. Epidemiologic studies suggest that Stx2 subtypes also differ in potency, but these differences have not been well documented for purified toxin. The relative potencies of five purified Stx2 subtypes, Stx2a, Stx2b, Stx2c, Stx2d, and activated (elastase-cleaved) Stx2d, were studied in vitro by examining protein synthesis inhibition using Vero monkey kidney cells and inhibition of metabolic activity (reduction of resazurin to fluorescent resorufin) using primary human renal proximal tubule epithelial cells (RPTECs). In both RPTECs and Vero cells, Stx2a, Stx2d, and elastase-cleaved Stx2d were at least 25 times more potent than Stx2b and Stx2c. In vivo potency in mice was also assessed. Stx2b and Stx2c had potencies similar to that of Stx1, while Stx2a, Stx2d, and elastase-cleaved Stx2d were 40 to 400 times more potent than Stx1.

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“…This toxin is responsible for the severe dehydrating diarrhea associated with cholera (48). EHEC produces similar toxins, known as verotoxins or Shiga toxins (Stx1 and Stx2), which are key virulence factors of the pathogen and are associated with the diarrhea, HC, and HUS characteristic of EHEC infection (4,10,58,61). These toxin genes are located on lambdoid prophages integrated into the bacterial genome (41,60).…”

mentioning

confidence: 99%

Bile Salts Induce Resistance to Polymyxin in Enterohemorrhagic Escherichia coliO157:H7

et al. 2011

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Many enteric bacteria use bile as an environmental cue to signal resistance and virulence gene expression. Microarray analysis of enterohemorrhagic Escherichia coli O157:H7 (EHEC) treated with bile salts revealed upregulation of genes for an efflux system (acrAB), a two-component signal transduction system (basRS/ pmrAB), and lipid A modification (arnBCADTEF and ugd). Bile salt treatment of EHEC produced a basS-and arnT-dependent resistance to polymyxin.

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Cytotoxic effect of Shiga toxin-2 holotoxin and its B subunit on human renal tubular epithelial cells

Cited by 57 publications

References 32 publications

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

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

Shiga Toxin Subtypes Display Dramatic Differences in Potency

Bile Salts Induce Resistance to Polymyxin in Enterohemorrhagic Escherichia coliO157:H7

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