Novel Biological Activity of Verotoxins: Induction of Cytokines.

弓形毒素/志贺毒素（Stx）在肠出血性大肠杆菌感染患者的溶血性尿毒症综合征（HUS）发病机制中起着至关重要的作用。细菌产生的Stx1和Stx2由于其对28S rRNA的n -糖苷酶活性而具有细胞毒性。在本研究中，我们发现Stx还具有诱导肠上皮细胞系Caco-2细胞产生促炎细胞因子的活性。Stx1和Stx2均能诱导IL-8、tnf - α、MCP-1 mrna，但Stx1的无毒突变体缺乏n-糖苷酶活性，不能诱导细胞因子mrna。在蛋白水平上，Stx1和Stx2增强了IL-8的产生，而突变体Stx1则没有。此外，与Stx酶活性相同的蓖麻毒素和莫德霉素等植物毒素也表现出细胞因子诱导活性。这些结果表明志贺毒素诱导Caco-2细胞细胞因子的表达和合成，其n -糖苷酶活性对诱导作用至关重要。

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.