Novel Biological Activity of Verotoxins: Induction of Cytokines.

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Verotoxin/Shiga toxin (Stx) plays a crucial role in the pathogenesis of hemolytic uremic syndrome (HUS) in patients infected with Enterohemorrhagic Escherichia coli. Stx1 and Stx2 produced by the bacteria are cytotoxic due to their N-glycosidase activity on 28S rRNA. In this study, we have shown that Stx also has the activity to induce the production of proinflammatory cytokines in Caco-2 cells, a intestinal epithelial cell line. Both Stx1 and Stx2 induce mRNAs of IL-8, TNFα, MCP-1, but non-toxic mutant of Stx1 which lacks N-glycosidase activity did not induce the cytokine mRNAs. IL-8 production at the protein level was enhanced by Stx1 and Stx2, but not by the mutant Stx1. In addition, plant toxins such as ricin and modeccin that have the same enzyme activity as Stx showed the cytokine-inducing activity. These results demonstrate that Shiga toxins induce expression and synthesis of cytokines in Caco-2 cells and their N-glyconsidase activity is essential for the induction.