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

在NADPH氧化酶(Nox)/双重氧化酶(DUOX)家族中，Nox1在人体组织中主要在结肠表达。原代培养的豚鼠胃粘膜细胞表达Nox1，当暴露于幽门螺杆菌(H.Pylori)I型脂多糖(LPS)时，其释放O2^-的速率要高得多，而不是来自毒力较低的II型菌株，提示Nox1可能参与了Hp相关疾病的发病机制。利用该培养体系，我们揭示了幽门螺杆菌内毒素刺激的胃粘膜细胞产生O_2~-需要两个不同的事件：NOX1及其新的组织者NOXO1的转录上调和rac1的激活(Am J Physiol，2005)。正常胃粘膜和慢性萎缩性胃炎不表达nox1和nox01，而在高分化腺癌、低分化腺癌和印戒细胞癌中特异性共表达，提示nox1和nox01可能是…。原代培养的豚鼠大肠上皮细胞表达Nox1、p22；lt；Phox&gt；、p67^&lt；Phox&gt；、NOx激活物1(NOXA1)、NOXO1和rac1，处于完全激活状态。NOXO1在T84细胞中的过表达增强了PMA刺激的超氧化物释放。肠炎沙门氏菌鞭毛蛋白可进一步促进Nox1蛋白的释放(J免疫)。Nox1蛋白在正常人结肠表面粘液细胞中呈结构性表达。Nox1蛋白在正常结肠和肿瘤中均呈成熟依赖性表达，其表达与有丝分裂活性无直接关系。然而，在富含κ蛋白的腺瘤和癌细胞中，NF-Nox1 B被激活。NOX1可能通过增加NF-κB依赖的抗凋亡特性而发挥促癌作用(癌症莱特，2005年)。在这个项目中，我介绍了NOX1在胃肠道的宿主防御和致癌中的潜在作用。较少

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