Arginine and polyamines in Helicobacter pylori-induced immune dysregulation and gastric carcinogenesis.
Arginine and polyamines in Helicobacter pylori-induced immune dysregulation and gastric carcinogenesis.
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DOI：
10.1007/s00726-011-1038-4
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发表时间：
2012-02
期刊：
影响因子：
3.5
通讯作者：
Wilson KT
中科院分区：
文献类型：
--
作者：
Chaturvedi R;de Sablet T;Coburn LA;Gobert AP;Wilson KT
l -精氨酸（L-Arg）由一氧化氮合酶和精氨酸酶代谢。胃病原体幽门螺杆菌引起消化性溃疡和胃癌。我们已经表明，l -精氨酸的可用性和代谢成多胺的改变显著地促进了宿主对这种感染的免疫反应失调。诱导型一氧化氮合酶（iNOS）产生的一氧化氮（NO）能杀死幽门螺杆菌。导致这一过程失败的机制有多种，包括幽门螺杆菌精氨酸酶对l -精氨酸底物的竞争，以及宿主巨噬细胞精氨酸酶II （Arg2）和鸟氨酸脱羧酶（ODC）的诱导。ODC生成精胺抑制iNOS翻译和no介导的幽门螺杆菌杀伤。ODC的表达依赖于独特AP-1复合物的形成，导致c-Myc作为转录增强子的上调。巨噬细胞凋亡是通过精胺氧化酶（SMO）氧化产生过氧化氢（H2O2）介导的，因此氧化应激诱导线粒体膜极化。我们的研究表明，凋亡是通过pERK→pc-Fos/c-Jun→c-Myc→ODC→SMO途径发生的。在胃上皮细胞中，幽门螺杆菌对氧化应激的激活依赖于SMO的诱导，并导致细胞凋亡和DNA损伤，因此抑制或敲除SMO可显著减轻这些事件。综上所述，精氨酸酶- odc途径的l -精氨酸代谢和SMO的激活可通过多胺介导的氧化应激和抗菌NO合成损伤导致幽门螺杆菌诱导的DNA损伤和免疫失调。我们的研究为幽门螺杆菌相关疾病（包括胃炎、溃疡疾病和胃癌）的治疗干预提供了新的靶点。
L-arginine (L-Arg) is metabolized by nitric oxide synthase and arginase enzymes. The gastric pathogen Helicobacter pylori causes peptic ulcer disease and gastric cancer. We have shown that alterations in L-Arg availability and metabolism into polyamines contribute significantly to the dysregulation of the host immune response to this infection. Nitric oxide (NO) derived from inducible NO synthase (iNOS) can kill H. pylori. There are multiple mechanisms leading to failure of this process, including competition for L-Arg substrate by H. pylori arginase, and induction of host macrophage arginase II (Arg2) and ornithine decarboxylase (ODC). Generation of spermine by ODC inhibits iNOS translation and NO-mediated H. pylori killing. Expression of ODC is dependent on formation of a unique AP-1 complex, leading to upregulation of c-Myc as a transcriptional enhancer. Macrophage apoptosis is mediated by oxidation of spermine via the enzyme spermine oxidase (SMO) that generates hydrogen peroxide (H2O2), and thus oxidative stress induced mitochondrial membrane polarization. Our studies have demonstrated that apoptosis occurs through a pERK→pc-Fos/c-Jun→c-Myc→ODC→SMO pathway. In gastric epithelial cells, activation of oxidative stress by H. pylori is dependent on SMO induction and results in both apoptosis and DNA damage, such that inhibition or knockdown of SMO markedly attenuates these events. In summary, L-Arg metabolism by the arginase-ODC pathway and the activation of SMO leads to H. pylori-induced DNA damage and immune dysregulation through polyamine-mediated oxidative stress and impairment of antimicrobial NO synthesis. Our studies indicate novel targets for therapeutic intervention in H. pylori-associated diseases, including gastritis, ulcer disease, and gastric cancer.