Study on the function of receptor for Helicobacter pylori VacA and the mechanism of its intoxication

幽门螺杆菌VacA受体功能及其中毒机制研究

• 批准号: 17209015
• 负责人: HIRAYAMA Toshiya
• 金额: $ 32.03万
• 依托单位: Nagasaki University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17209015/
• 关键词: Helicobacter pylori; VacA; AZ-521 cells; COX-2; PGE_2; p38 MAP kinase; ATF-2 cascade; Bacterial toxin; Pathogenesis

By 2006 budget, we found that VacA increases PGE_2 production by AZ-521 cells by up-regulation of COX-2 expression through a signaling pathway involving the p38 MAP kinase/ATF-2 cascade, leading to activation of the CRE element on the COX-2 promoter.Treatment of AZ-521 cells with Helicobacter pylori VacA increased cyclooxygenase-2 (COX-2) mRNA in a time-and dose-dependent manner. A p38 MAP kinase (MAPK) inhibitor, SB203580, blocked elevation of COX-2 mRNA levels, whereas PD98059, which blocks the Erkl/2 cascade, partially suppressed the increase. Consistent with involvement of p38 MAPK, VacA-induced accumulation of COX-2 mRNA was reduced in AZ-521 cells overexpressing a dominant-negative p38 MAPK (DN-p38). Phosphatidylinositol-specific phospholipase C, which inhibits VacA-induced p38 MAPK activation, blocked VacA-induced COX-2 expression. In parallel with COX-2 expression, VacA increased PGE_2 production, which was inhibited by SB203580 and NS-398, a COX-2 inhibitor. VacA-induced PGE2 production was markedly attenuated in AZ-521 cells stably expressing DN-p38. VacA increased transcription of a COX-2 promoter reporter gene and activated a COX-2 promoter containing mutated NF-kB or NF-IL6 sites, but not a mutated CRE site, suggesting direct involvement of the ATF-2/CREB-binding region in VacA-induced COX-2 promoter activation. The reduction of ATF-2 expression in AZ-521 cells transformed with ATF-2-siRNA resulted in suppression of COX-2 expression. Thus, we found that VacA enhances PGE_2 production by AZ-521 cells through induction of COX-2 expression via the p38 MAPK /ATF-2 cascade, leading to activation of the CRE site in the COX-2 promoter.

到2006年，我们发现VacA通过p38 MAP激酶/ATF-2级联信号通路上调考克斯-2表达，激活考克斯-2启动子上的CRE元件，从而增加AZ-521细胞PGE_2的产生，并且VacA以时间和剂量依赖的方式增加COX-2（考克斯-2）mRNA。p38 MAP激酶（MAPK）抑制剂SB 203580阻断了考克斯-2 mRNA水平的升高，而阻断Erk 1/2级联的PD 98059部分抑制了该升高。与p38 MAPK的参与一致，在过表达显性阴性p38 MAPK（DN-p38）的AZ-521细胞中，VacA诱导的考克斯-2 mRNA的积累减少。磷脂酰肌醇特异性磷脂酶C抑制VacA诱导的p38 MAPK活化，阻断VacA诱导的考克斯-2表达。与考克斯-2的表达平行，VacA增加PGE_2的产生，这被SB 203580和NS-398（考克斯-2抑制剂）抑制。在稳定表达DN-p38的AZ-521细胞中，VacA诱导的PGE 2产生显著减弱。VacA增加了考克斯-2启动子报告基因的转录，并激活了含有突变的NF-κ B或NF-IL 6位点的考克斯-2启动子，但没有突变的CRE位点，表明ATF-2/CREB结合区直接参与了VacA诱导的考克斯-2启动子激活。ATF-2-siRNA转染的AZ-521细胞中ATF-2表达的降低导致考克斯-2表达的抑制。因此，我们发现VacA通过p38 MAPK /ATF-2级联反应诱导考克斯-2表达，从而激活考克斯-2启动子中的CRE位点，从而增强AZ-521细胞PGE_2的产生。

项目成果

Helicobacter pylori VacA clustering in lipid rafts, mediated by receptor, RPTP is required for intoxication in AZ-521 cells.

幽门螺杆菌 VacA 在脂筏中聚集，由受体 RPTP 介导，是 AZ-521 细胞中毒所必需的。

• 发表时间: 2006
• 期刊: Infect Immun. 74
• 作者: Nakayama M.;et al.
• 通讯作者: et al.

Endoscope disinfection using chlorine dioxide in an automated washer-disinfector

• DOI: 10.1016/j.jhin.2006.01.020
• 发表时间: 2006-07-01
• 期刊: JOURNAL OF HOSPITAL INFECTION
• 影响因子: 6.9
• 作者: Isomoto, H.;Urata, M.;Kohno, S.
• 通讯作者: Kohno, S.

Helicobacter pylori vacuolating cytotoxin induces activation of the proapoptotic protein Bax, leading to cytochrome c release and cell death, independent of vacuolation

幽门螺杆菌空泡细胞毒素诱导促凋亡蛋白 Bax 的激活，导致细胞色素 c 释放和细胞死亡，与空泡形成无关

• 发表时间: 2006
• 期刊: J. Biol. Chem. 281
• 作者: Yamasaki E.;et al.
• 通讯作者: et al.

Functional antagonism between Helicobacter pylori CagA and VacA in control of the NFAT signaling pathway in gastric epithelial cells

幽门螺杆菌 CagA 和 VacA 之间的功能拮抗作用控制胃上皮细胞 NFAT 信号通路

• 发表时间: 2005
• 期刊: Proc.Natl.Acad.Sci.USA. 102
• 作者: Yokoyama;K.;et al.
• 通讯作者: et al.

High concentrations of human beta-defensin 2 in gastric juice of patients with Helicobacter pylori infection.

幽门螺杆菌感染患者胃液中人β-防御素2浓度高。

• 发表时间: 2005
• 期刊: World J Gastroenterol 11
• 作者: Isomoto H;Mukae H;Ishimoto H;Nishi Y;Wen CY;Wada A;Ohnita K;Hirayama T;Nakazato M;Kohno S
• 通讯作者: Kohno S