Shiga Toxin Produced by Enterohemorrhagic Escherichia coli Inhibits Pi3K/Nf-B Signaling Pathway in Globotriaosylceramide-3-Negative Human Intestinal Epithelial Cells

Gobert, A.P.; Vareille, M.; Glasser, A.-L.; Hindre, T.; de Sablet, T.; Martin, C.

The Journal of Immunology 178(12): 8168-8174

2007


DOI: 10.4049/jimmunol.178.12.8168
Accession: 068490491

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Abstract
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-kappaB 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-kappaB DNA-binding activity. Consequently, the NF-kappaB-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-kappaB 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 DeltaStx-infected T84 cells yielded to a complete decrease of NF-kappaB activation and CCL20 and IL-8 mRNA expression. This demonstrates that the induction of the PI3K/Akt/NF-kappaB 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.