Shiga toxin 1 elicits diverse biologic responses in mesangial cells

Simon, Matthias; Cleary, Thomas G.; Hernandez, James D.; Abboud, Hanna E.

doi:10.1046/j.1523-1755.1998.00085.x

Cited by 56 publications

(27 citation statements)

References 43 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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“…Indeed, one model of Stx-mediated disease in mice requires the co-administration of LPS and Stx (50). Several means by which inflammatory cytokines may promote systemic disease have been proposed, including induction of the Gb 3 glycolipid Stx receptor on host cells (89)(90)(91), alteration of fibrinolysis and anticoagulation, or recruitment of inflammatory cells into damaged tissues (77). In response to Stx, cultured monocytes secrete TNF-α and IL-6 (90,92,93), and we found that these cytokines were elevated in the serum or kidneys of mice infected with C. rodentium (λstx 2dact ).…”

Section: Discussionmentioning

confidence: 99%

A novel murine infection model for Shiga toxin–producing Escherichia coli

Mallick

McBee²,

Vanguri³

et al. 2012

J. Clin. Invest.

118

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Enterohemorrhagic E. coli (EHEC) is an important subset of Shiga toxin-producing (Stx-producing) E. coli (STEC), pathogens that have been implicated in outbreaks of food-borne illness and can cause intestinal and systemic disease, including severe renal damage. Upon attachment to intestinal epithelium, EHEC generates "attaching and effacing" (AE) lesions characterized by intimate attachment and actin rearrangement upon host cell binding. Stx produced in the gut transverses the intestinal epithelium, causing vascular damage that leads to systemic disease. Models of EHEC infection in conventional mice do not manifest key features of disease, such as AE lesions, intestinal damage, and systemic illness. In order to develop an infection model that better reflects the pathogenesis of this subset of STEC, we constructed an Stx-producing strain of Citrobacter rodentium, a murine AE pathogen that otherwise lacks Stx. Mice infected with Stx-producing C. rodentium developed AE lesions on the intestinal epithelium and Stx-dependent intestinal inflammatory damage. Further, the mice experienced lethal infection characterized by histopathological and functional kidney damage. The development of a murine model that encompasses AE lesion formation and Stx-mediated tissue damage will provide a new platform upon which to identify EHEC alterations of host epithelium that contribute to systemic disease.

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“…In addition to inducing TNF-␣, Stx has been shown to induce chemokine production in some types of cells (34,42). For example, Simon et al (30) reported that Stx1 induced monocyte chemoattractant protein 1 production in cultured human mesangial cells. Stx1 also induced the expression of adhesion molecules in endothelial cells (19).…”

Section: Discussionmentioning

confidence: 99%

Shiga Toxin 1 Causes Direct Renal Injury in Rats

et al. 2005

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Infection with Shiga toxin (Stx)-producing Escherichia coli has been implicated to cause hemolytic uremic syndrome, which is characterized by histological abnormalities such as microvascular thrombi and tubular cell damage in the kidney. Although Stx is known to be the major virulence factor of the pathogen, it is still unclear whether Stx directly impairs renal cells in vivo to cause such histological changes and deterioration of renal function. To assess the consequence of the direct action of Stx on renal cells, left kidneys of rats were perfused with Stx1 from the renal artery through the renal vein and then revascularized. Kidneys of control animals were perfused with the vehicle alone. On day 1, apoptosis and induction of tumor necrosis factor alpha gene expression were noticed to occur in the medulla of the Stx1-perfused kidneys. On day 3, extensive tubular injuries were observed by light microscopy: aggregated platelets and monocytic infiltrates in both glomeruli and the medullary interstitium were detected by immunostaining. Tubular changes were more extensive on day 9, with areas of infarction seen in the cortex and medulla. These changes were not found to occur in the sham-operated kidneys. No obvious glomerular changes were detected by light microscopy at any time point. When nonperfused right kidneys were removed after the Stx1 perfusion of the left kidneys, the serum creatinine and blood urea nitrogen levels were increased from day 2, and acute renal failure followed on day 3. These results indicate that Stx1 caused glomerular platelet aggregation, tubular damage, and acute deterioration of renal function by acting directly on renal cells.

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Shiga toxin 1 elicits diverse biologic responses in mesangial cells

Cited by 56 publications

References 43 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

A novel murine infection model for Shiga toxin–producing Escherichia coli

Shiga Toxin 1 Causes Direct Renal Injury in Rats

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