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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

豚鼠胃凹细胞表达 gp91-phox、丝裂原氧化酶 1 (Mox1) 的同工酶和吞噬细胞 NADPH 氧化酶的必需成分（p67- 和 p22-phoxes）。它们自发释放超氧阴离子 (<O_2>^-)。在培养的最初 2 天中，过氧化氢酶显着抑制 [^3H]胸苷摄取。通过超氧化物歧化酶加过氧化氢酶或N-乙酰半胱氨酸清除<O_2>^-和相关氧化剂并通过二亚苯基碘鎓抑制Moxl氧化酶激活caspase 3样蛋白酶并显着增强细胞凋亡。这种加速的细胞凋亡被半胱天冬酶抑制剂 z-Val-Ala-Asp-CH2F 完全阻断。 Mox1 衍生的活性氧中间体组成型激活核因子 κB (NF-κB)，并且 NF-kB 诱饵寡脱氧核苷酸抑制这种活性加速了它们的自发凋亡。这些结果表明，凹细胞 Moxl 氧化酶产生的 <O_2>^- 可能在调节其自发凋亡以及细胞增殖中发挥至关重要的作用。幽门螺杆菌 (Hp) 脂多糖 (LPS) 已被证明可作为 Mox1 氧化酶的有效激活剂。这些细胞在无LPS的条件下自发地分泌约10nmol<O_2>^-/mg蛋白质/h。他们以 2.1 内毒素单位/ml 或更高浓度表达 Toll 样受体 4 (TLR4) mRNA 和来自 I 型 Hp 的 LPS，刺激 TRL4 介导的转化生长因子-b 激活激酶 1 及其结合蛋白 1 的磷酸化，诱导 p67-phox，并将 <O_2>^- 产生上调 10 倍。相反，来自cag致病性岛的完全或部分缺失突变体的Hp LPS不会促进这些事件。脂质A被证实是具有启动效应的生物活性成分。用来自NCTC 11637的LPS以>2.1内毒素单位/ml处理豚鼠胃粘膜细胞引起细胞凋亡。 LPS 的脂质 A 介导了这种细胞凋亡。 Hp LPS 刺激 Toll 样受体 4 (TLR4) 和磷酸化转化生长因子-b 激活激酶 1 (TAK1)、TAK1 结合蛋白 1 和 c-Jun N 末端激酶 (JNK) 2。我们的结果表明，IHp 脂质 A 可能通过刺激 TLR4 级联，成为胃粘膜增殖和凋亡的有效调节剂和窝细胞中的 Mox1 氧化酶。较少的