| Project/Area Number |
12670491
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | The University of Tokushima |
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Principal Investigator |
ROKUTAN Kazuhito The University of Tokushima, School od Medicine, Associate Professor, 医学部, 助教授 (10230898)
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| Project Period (FY) |
2000 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2001: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2000: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Keywords | 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 |
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| Research Abstract |
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
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