Induction of cytokines in a human colon epithelial cell line by Shiga toxin 1 (Stx1) and Stx2 but not by non‐toxic mutant Stx1 which lacks <i>N</i>‐glycosidase activity

Yamasaki, Chisato; Natori, Yumiko; Zeng, Xun-Ting; Ohmura, Mari; Yamasaki, Shinji; Takeda, Yoshifumi; Natori, Yasuhiro

doi:10.1016/s0014-5793(98)01667-6

Cited by 86 publications

(76 citation statements)

References 31 publications

(32 reference statements)

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“…Stx induces apoptosis and/or necrosis of Gb-3-presenting cells, i.e., renal microvascular endothelial cells and several epithelial cell lines, by altering ribosomal functions. Paradoxically, this general blockade of mRNA translation is associated with the inducible release of various mediators of the inflammation (15,16). Several data support the concept that the Stx-dependent upregulation of proinflammatory genes in Gb3-positive epithelial cell lines occurs through the ribotoxic stress response since Stx, and other compounds possessing an N-glycosidase activity, induces cytokine release (25).…”

Section: Discussionmentioning

confidence: 99%

“…EHEC factors, e.g., flagellin or proteins encoded by the locus of enterocyte effacement, have been shown to modulate NF-B activation (14). More particularly, some studies support the notion that Stx might stimulate the innate immune response (15,16). Nonetheless, the experiments have been performed with Gb-3-expressing cell lines, and according to the duration of the stimulation and the Stx concentration, various results have been obtained (9).…”

Section: S Higa Toxin Producing Escherichia Coli (Stec)mentioning

confidence: 99%

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Shiga Toxin Produced by Enterohemorrhagic Escherichia coli Inhibits PI3K/NF-κB Signaling Pathway in Globotriaosylceramide-3-Negative Human Intestinal Epithelial Cells

Gobert

Vareille

Glasser³

et al. 2007

The Journal of Immunology

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Shiga toxin (Stx) produced by enterohemorrhagic Escherichia coli (EHEC) binds to endothelial cells expressing globotriaosylceramide-3 (Gb-3) and induces cell death by inhibiting translation. Nonetheless, the effects of Stx on human enterocytes, which lacks receptor Gb-3, remain less known. In this study, we questioned whether EHEC-derived Stx may modulate cellular signalization in the Gb-3-negative human epithelial cell line T84. Stx produced by EHEC was fixed and internalized by the cells. A weak activation of NF-κB was observed in T84 cells after EHEC infection. Cells infected with an isogenic mutant lacking stx1 and stx2, the genes encoding Stx, displayed an increased NF-κB DNA-binding activity. Consequently, the NF-κB-dependent CCL20 and IL-8 gene transcription and chemokine production were enhanced in T84 cells infected with the Stx mutant in comparison to the wild-type strain. Investigating the mechanism by which Stx modulates NF-κB activation, we showed that the PI3K/Akt signaling pathway was not induced by EHEC but was enhanced by the strain lacking Stx. Pharmacological inhibition of the PI3K/Akt signalization in EHEC ΔStx-infected T84 cells yielded to a complete decrease of NF-κB activation and CCL20 and IL-8 mRNA expression. This demonstrates that the induction of the PI3K/Akt/NF-κB pathway is potentially induced by EHEC, but is inhibited by Stx in Gb-3-negative epithelial cells. Thus, Stx is an unrecognized modulator of the innate immune response of human enterocytes.

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Section: Discussionmentioning

confidence: 99%

Section: S Higa Toxin Producing Escherichia Coli (Stec)mentioning

confidence: 99%

Shiga Toxin Produced by Enterohemorrhagic Escherichia coli Inhibits PI3K/NF-κB Signaling Pathway in Globotriaosylceramide-3-Negative Human Intestinal Epithelial Cells

Gobert

Vareille

Glasser³

et al. 2007

The Journal of Immunology

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“…The highest concentrations were detected in the blood of patients who died during the acute phase of disease (124). Stx may induce IL-8 secretion from intestinal epithelial cells (152,153) and thus prime the inflammatory response in the intestine, leading to increased chemotaxis and further activation of inflammatory cells. Increased serum levels of granulocyte colony-stimulating factor (126,143) and monocyte chemoattractant protein-1 (7) have also been found.…”

Section: Host Responsementioning

confidence: 99%

Pathogenesis of Shiga Toxin-Associated Hemolytic Uremic Syndrome

2001

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“…The assay for Stx binding to Gb 3 was performed as described (16). Porcine erythrocyte Gb 3 (500 ng; Wako Pure Industries) was applied to an HPTLC plate (Whatman) and developed in chloroform͞methanol͞water (60:35:8, vol͞vol).…”

Section: S Higa Toxin (Stx)-producing Escherichia Coli (Stec) Includ-mentioning

confidence: 99%

A therapeutic agent with oriented carbohydrates for treatment of infections by Shiga toxin-producing Escherichia coli O157:H7

Nishikawa

Matsuoka

Kita

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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186

125

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Infection with Shiga toxin (Stx)-producing Escherichia coli O157:H7, which causes diarrhea and hemorrhagic colitis in humans, often results in fatal systemic complications, such as neurological damage and hemolytic-uremic syndrome. Because Stx circulating in the blood is a major causative factor of these complications, the development of a Stx neutralizer that functions in the circulation holds promise as a viable therapy. Here we developed a series of carbosilane dendrimers, in which trisaccharides of globotriaosyl ceramide, a receptor for Stx, were variously oriented at their termini (referred to as SUPER TWIG), and identified a SUPER TWIG with six trisaccharides as a Stx neutralizer functioning in the circulation. This SUPER TWIG specifically bound to Stx with high affinity (Kd ‫؍‬ 1.1 ؋ 10 ؊6 M) and inhibited the incorporation of the toxin into target cells. Intravenous administration of the SUPER TWIG along with Stx to mice substantially reduced the fatal brain damage and completely suppressed the lethal effect of Stx. Moreover, the SUPER TWIG protected mice from challenge with a fatal dose of E. coli O157:H7, even when administered after the establishment of the infection. The SUPER TWIG neutralized Stx in vivo by a mechanism in which the accumulation and immediate degradation of Stx by phagocytic macrophages present in the reticuloendothelial system were induced. Taken together, our findings indicate that this SUPER TWIG is therapeutic agent against infections by Stx-producing E. coli.

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Induction of cytokines in a human colon epithelial cell line by Shiga toxin 1 (Stx1) and Stx2 but not by non‐toxic mutant Stx1 which lacks N‐glycosidase activity

Cited by 86 publications

References 31 publications

Shiga Toxin Produced by Enterohemorrhagic Escherichia coli Inhibits PI3K/NF-κB Signaling Pathway in Globotriaosylceramide-3-Negative Human Intestinal Epithelial Cells

Shiga Toxin Produced by Enterohemorrhagic Escherichia coli Inhibits PI3K/NF-κB Signaling Pathway in Globotriaosylceramide-3-Negative Human Intestinal Epithelial Cells

Pathogenesis of Shiga Toxin-Associated Hemolytic Uremic Syndrome

A therapeutic agent with oriented carbohydrates for treatment of infections by Shiga toxin-producing Escherichia coli O157:H7

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