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Roll of TLR-mediated activation of Mox1 oxidase in innate immunity and carcinogenesis of the gastrointestinal tract

TLR介导的Mox1氧化酶激活在先天免疫和胃肠道癌发生中的作用

基本信息

批准号：
14370184
负责人：
ROKUTAN Kazuhito
金额：
$ 7.3万
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 (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370184/
关键词：
Toll-like receptor NADPH oxidase 1 gastrointestinal epithelium reactive oxygen species innate immunity carcinogenesis Helicobacter pylori flagellin 活性酵素

项目摘要

Among the NADPH oxidase (Nox)/Dual oxidase (Duox) family, Nox1 is dominantly expressed in the colon among human tissues. Guinea pig gastric mucosal cells in primary culture express Nox1 and are able to release O_2^- at much higher rates when exposed to Helicobacter pylori (H. pylori) lipopolysaccharide (LPS) from type I, but not from less virulent type II strains, suggesting that Nox1 may be involved in the pathogenesis of H. pylori-associated diseases. Using this culture system, we have revealed that the H. pylori LPS-stimulated O_2^- production in gastric mucosal cells require two distinct events : transcriptional up-regulation of Nox1 and its novel organizer NOXO1, and activation of Rac1 (Am J Physiol, 2005). Normal human gastric mucosa or chronic atrophic gastritis did not express Nox1 and NOXO1, while these mRNAs and proteins were specifically co-expressed in well and poorly differentiated adenocarcinomas as well as signet-ring cell carcinomas, suggesting that Nox1 and NOXO1 may b … More e associated with inflammation- and ROS-related carcinogenesis in Helicobacter pylori-infected stomach.Primary cultures of guinea pig large intestinal epithelial cells constitutively expressed Nox1, p22^<phox>, p67^<phox>, Nox activator 1 (NOXA1), NOXO1, and Rac1, and this oxidase was in a fully activated status. Overexpression of NOXO1 in T84 cells enhanced PMA-stimulated superoxide release. Flagellin from Salmonella enteritidis further augmented the release in association with the induction of Nox1 protein (J Immunol). Nox1 protein was constitutively expressed in surface mucous cells of the normal human colon. Nox1 protein showed maturation-dependent expression in both normal colon and tumors, and its expression was not directly linked to mitogenic activities. However, NF-κB was activated in adenoma and carcinoma cells possessing abundant Nox1 protein. Nox1 may exert a cancer-promoting effect by increasing NF-κB-dependent anti-apoptotic properties (Cancer Lett, 2005).In this project, I have introduced potential roles of Nox1 in host defense and carcinogenesis in the gastrointestinal tract. Less

在NADPH氧化酶（Nox）/双氧化酶（Duox）家族中，Nox 1在人体组织中主要表达于结肠。原代培养的豚鼠胃粘膜细胞表达Nox 1，当暴露于幽门螺杆菌（H. pylori）脂多糖（LPS）的表达，而对弱毒力的II型菌株则无表达，提示Nox 1可能参与了H.幽门相关疾病利用这一培养体系，我们发现H。幽门螺杆菌LPS刺激胃粘膜细胞产生O_2 ~-需要两个不同的过程：Nox 1及其新组织者NOXO 1的转录上调和Rac 1的激活（Am J Physiol，2005）。正常人胃粘膜或慢性萎缩性胃炎不表达Nox 1和NOXO 1，而这些mRNA和蛋白在高分化和低分化腺癌以及印戒细胞癌中特异性共表达，表明Nox 1和NOXO 1可能与B ...更多信息原代培养的豚鼠大肠上皮细胞组成性表达Nox 1、p22^<phox>、p67^<phox>、Nox激活物1（NOXA 1）、NOXO 1和Rac 1，且该氧化酶处于完全激活状态。NOXO 1在T84细胞中的过表达增强PMA刺激的超氧化物释放。来自沙门氏菌的鞭毛蛋白进一步增强了与Nox 1蛋白诱导相关的释放（J Immunol）。Nox 1蛋白在正常人结肠黏膜细胞中呈组成型表达。Nox 1蛋白在正常结肠和肿瘤中均表现出成熟依赖性表达，其表达与促有丝分裂活性无直接关系。而NF-κB在富含Nox 1蛋白的腺瘤和癌细胞中被激活。Nox 1可能通过增加NF-κ B依赖的抗凋亡特性而发挥促癌作用（Cancer Lett，2005）。少