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

点击翻译按钮获取中文摘要

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