Regulation of growth and death of gastric epithelial cells by Toll-like receptors and the mox1 gene.

Toll 样受体和 mox1 基因对胃上皮细胞生长和死亡的调节。

基本信息

批准号：
12670491
负责人：
ROKUTAN Kazuhito
金额：
$ 2.43万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670491/
关键词：
mitogen oxidase 1 Toll-like receptor 4 gastric epithelial cells gastric cancer apoptosis abnormal cell growth Helicobacter pylori infection NF-κB 増殖活性酸素 lipopolysaccharide 細胞内シグナル

项目摘要

Guinea pig gastric pit cells express an isozyme of gp91-phox, mitogen oxidase 1 (Mox1) and essential components for the phogocyte NADPH oxidase (p67- and p22-phoxes). They spontaneously release superoxide anion (<O_2>^-). Catalase significantly inhibited [^3H]thymidine uptake during the initial 2 days of culture. Scavenging <O_2>^- and related oxidants by superoxide dismutase plus catalase or N-acetyl cysteine and inhibiting Moxl oxidase by diphenylene iodonium activated caspase 3-like proteases and markedly enhanced apoptosis. This accelerated apoptosis was completely blocked by a caspase inhibitor, z-Val-Ala-Asp-CH2F. Mox1-derived reactive oxygen intermediates constitutively activated nuclear factor κB (NF-κB), and inhibition of this activity by NF-kB decoy oligodeoxynucleotide accelerated their spontaneous apoptosis. These results suggest that <O_2>^- produced by the pit cell Moxl oxidase may play a crucial role in the regulation of their spontaneous apoptosis as well as cell prolif … More eration.Helicobacter pylori (Hp) lipopolysaccharide (LPS) have been shown to function as potent activators for the Mox1 oxidase. These cells spontaneously secreted about 10 nmol <O_2>^-/mg protein/h in LPS-free conditions. They expressed the Toll-like receptor 4 (TLR4) mRNA, and LPS from type I Hp at 2.1 endotoxin unit/ml or higher stimulated TRL4-mediated phosphorylations of transforming growth factor-b -activated kinase 1 and its binding protein 1, induced p67-phox, and up-regulated <O_2>^- production 10-fold. In contrast, none of these events were promoted with Hp LPS from complete or partial deletion mutants of the cag pathogenicity island. Lipid A was confirmed to be a bioactive component for the priming effects Treatment of guinea pig gastric mucosal cells with LPS from NCTC 11637 at > 2.1 endotoxin unit/ml causedapoptosis. Lipid A of the LPS mediated this apoptosis. Hp LPS stimulated the Toll-like receptor 4 (TLR4) and phosphorylated transforming growth factor-b -activated kinase 1 (TAK1), TAK1 binding protein 1, and c-Jun N-terminal kinase (JNK) 2.Our results suggest that type IHp lipid A may be a potent regulator for proliferation and apoptosis of gastric mucosa by stimulating TLR4 cascade and Mox1 oxidase in pit cells. Less

豚鼠胃坑细胞表达gp91-Phox，有丝分裂原氧化酶1（MOX1）的同工酶和1HADPH氧化酶（p67-和p22-Phoxes）的必需成分。他们赞助释放超氧化物阴离子（<O_2>^ - ）。过氧化氢酶在培养的最初2天内显着抑制[^3H]胸苷的摄取。通过超氧化物歧化酶，过氧化氢酶或N-乙酰半胱氨酸清除<O_2>^ - 和相关的氧化物，并通过二苯基碘激活的caspase 3-like蛋白酶抑制MOXL氧化酶，并显着增强了细胞凋亡。 caspase抑制剂Z-VAL-ALA-ASP-CH2F完全阻断了这种加速凋亡。 MOX1衍生的活性氧中间体组成性活化的核因子κB（NF-κB），NF-KB诱饵寡脱氧核苷酸对这种活性的抑制加速了其赞助子凋亡。这些结果表明，由坑细胞Moxl氧化酶产生的<O_2>^ - 可能在调节其赞助凋亡以及细胞增殖中起关键作用。这些细胞在无LPS条件下赞助分泌约10 nmol <O_2>^ - /mg蛋白/H。他们表达了类似TOLL的受体4（TLR4）mRNA，以及来自I型HP的LPS 2.1内毒素单位/mL或更高的刺激TRL4介导的TRL4介导的磷酸化，用于转化生长因子-B-B激活激活的激酶1及其结合蛋白1（其结合蛋白1），诱导的p67- phox phox phox，并上调了<O_2>^-2>^-2>^-2-^-2-ford。相比之下，这些事件均未通过CAG致病岛的完整或部分缺失突变体的HP LP促进。脂质A被确认为用于用NCTC 11637> 2.1内毒素单位/ML造成病毒的NCTC 11637的LPS对豚鼠胃粘膜细胞进行启动作用治疗的生物活性成分。 LPS的脂质A介导了这种凋亡。 Hp LPS stimulated the Toll-like receptor 4 (TLR4) and phosphorylated transforming growth factor-b -activated kinase 1 (TAK1), TAK1 binding protein 1, and c-Jun N-terminal kinase (JNK) 2.Our results suggest that type IHp lipid A may be a potential regulator for proliferation and apoptosis of gastric mucosa by stimulating TLR4 cascade and坑细胞中的MOX1氧化酶。较少的