Novel Biological Activity of Verotoxins: Induction of Cytokines.

• Project/Area Number: 10672120
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Environmental pharmacy
• Research Institution: International Medical Center of Japan
• Principal Investigator: NATORI Yasuhiro (1999) Director, Department of Clinical Pharmacology, International Medical Center of Japan, 臨床薬理研究部, 部長 (10164485); 名取 有美子 (1998) 国立国際医療センター研究所, 臨床薬理研究部, 室長 (40107389)
• Co-Investigator(Kenkyū-buntansha): 名取 泰博 国立国際医療センター研究所, 臨床薬理研究部, 部長 (10164485)
• Project Period (FY): 1998 – 1999
• Project Status: Completed (Fiscal Year 1999)
• Budget Amount: ¥3,000,000 (Direct Cost: ¥3,000,000); Fiscal Year 1999: ¥1,100,000 (Direct Cost: ¥1,100,000); Fiscal Year 1998: ¥1,900,000 (Direct Cost: ¥1,900,000)
• Keywords: Verotoxins / Enterohemorrhagic Escherichia coli / Cytokines / Inestinal epithelial cell

Research Abstract

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.

Research Products

• [Publications] Z. L. Ou: "Transient and Sequential Expression of Chemokine mRNA in glomeruli in Puromycin Aminonucleoside Nephrosis"Nephron. (in press). (2000)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] C.Yamasaki, Yu.Natori, X.-T.Zeng, M.Omura, S.Yamasaki, Y.Takeda and Y.Natori: "Introduction 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."FEBS Lett.. 442(2-3). 231-234 (1999)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Z. L. Ou: "Transient and Sequential Expression of Chemokine mRNA in glomeruli in Puromycin Aminonuclooside Nephrosis"Nephron. (in press). (2000)
• [Publications] C.yamasaki et al: "Induction of cytokines in a human colon epithelial call line by Shiga torin-(Stx1)and Stx2 but not by non-taxic mutant Stx1" FEBS Lett.442・2-3. 231-234 (1999)