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，Nox1 主要在人体组织的结肠中表达，原代培养物中的豚鼠胃粘膜细胞表达 Nox1，并且在暴露时能够以更高的速率释放 O_2^-。 I 型幽门螺杆菌 (H. pylori) 脂多糖 (LPS)，但不包括毒性较弱的 II 型菌株，表明 Nox1 可能参与幽门螺杆菌相关疾病的发病机制。使用该培养系统，我们发现胃粘膜细胞中幽门螺杆菌 LPS 刺激的 O_2^- 产生需要两个不同的事件：转录上调。 -Nox1 及其新型组织者 NOXO1 的调节以及 Rac1 的激活（Am J Physiol，2005）。正常人胃粘膜或慢性萎缩性胃炎。不表达Nox1和NOXO1，而这些mRNA和蛋白质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Nox1和NOXO1可能与炎症和ROS相关幽门螺杆菌感染胃的致癌作用。豚鼠大肠上皮细胞的原代培养物组成型表达Nox1， p22^<phox>、p67^<phox>、Nox 激活剂 1 (NOXA1)、NOXO1 和 Rac1，并且该氧化酶在 T84 细胞中处于完全激活状态，增强了沙门氏菌 PMA 刺激的鞭毛蛋白释放。肠炎杆菌进一步增强了与 Nox1 蛋白诱导相关的释放（Nox1 蛋白）。 Nox1蛋白在正常结肠和肿瘤中均表现出成熟依赖性表达，并且其表达与促有丝分裂活性没有直接关系，然而，在具有丰富Nox1蛋白的腺瘤和癌细胞中，NF-κB被激活，可能发挥促癌作用。通过增加 NF-κB 依赖性抗凋亡特性（Cancer Lett，2005）。在这个项目中，我Less 介绍了 Nox1 在宿主防御和胃肠道癌发生中的潜在作用。