Novel Biological Activity of Verotoxins: Induction of Cytokines.

维罗毒素/志贺毒素(STX)在肠出血性大肠埃希菌感染患者的溶血性尿毒症(HUS)发病机制中起重要作用。该细菌产生的STX1和STX2具有细胞毒性，因为它们对28S rRNA具有N-糖苷酶活性。在这项研究中，我们已经证明了STX还具有诱导肠道上皮细胞系Caco-2细胞产生促炎细胞因子的活性。Stx1和Stx2均可诱导IL-8、肿瘤坏死因子α、单核细胞趋化蛋白-1mRNAs的表达，但无N-糖苷酶活性的无毒突变株不能诱导细胞因子mRNAs的产生。在蛋白质水平上，STX1和StX2可促进IL-8的产生，但突变体STX1不能促进IL-8的产生。此外，与STX具有相同酶活性的植物毒素，如蓖麻毒素和莫德霉素，也显示出细胞因子诱导活性。这些结果表明，志贺毒素诱导Caco-2细胞表达和合成细胞因子，其N-糖苷酶活性在诱导过程中是必不可少的。

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.