Induction of polyamine oxidase 1 by Helicobacter pylori causes macrophage apoptosis by hydrogen peroxide release and mitochondrial membrane depolarization
Induction of polyamine oxidase 1 by Helicobacter pylori causes macrophage apoptosis by hydrogen peroxide release and mitochondrial membrane depolarization
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DOI：
10.1074/jbc.m401370200
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发表时间：
2004-09-17
影响因子：
4.8
通讯作者：
Wilson, KT
中科院分区：
文献类型：
--
作者：
Chaturvedi, R;Cheng, YL;Wilson, KT
幽门螺杆菌通过逃避宿主的免疫反应感染人类的胃。细菌存活和粘膜损伤的一种机制是诱导巨噬细胞凋亡，我们已经报道了巨噬细胞凋亡依赖于精氨酸酶和鸟氨酸脱羧酶合成多胺。在代谢反转化过程中，多胺被氧化释放H2O2，通过线粒体膜去极化导致细胞凋亡。我们假设这种机制是由巨噬细胞中的幽门螺杆菌诱导的。在乙酰多胺氧化酶进行反转化之前，可通过亚精胺/精胺n -1乙酰转移酶对精胺或亚精胺进行乙酰化，但最近已证实，人多胺氧化酶h1（也称为精胺氧化酶）直接将精胺转化为亚精胺。幽门螺杆菌诱导该酶的小鼠同源物（多胺氧化酶1 (PAO1)）的表达和活性与鸟氨酸脱羧酶平行6 h，与凋亡的开始一致，而亚精胺/精胺n -1乙酰转移酶的活性延迟至18 h，此时晚期凋亡已经达到峰值。MDL 72527或PAO1小干扰RNA抑制PAO1可显著减弱幽门螺杆菌诱导的细胞凋亡。抑制PAO1也显著降低H2O2的产生、线粒体膜去极化、细胞色素c的释放和caspase-3的激活。瞬时转染过表达PAO1诱导巨噬细胞凋亡。过氧化氢酶对细胞凋亡的抑制作用证实了H2O2的重要性。这些研究证明了病原体诱导巨噬细胞氧化应激的新机制，其中PAO1的激活通过线粒体依赖的细胞死亡途径导致H2O2释放和凋亡，从而导致幽门螺杆菌感染等疾病的宿主防御缺陷。
Helicobacter pylori infects the human stomach by escaping the host immune response. One mechanism of bacterial survival and mucosal damage is induction of macrophage apoptosis, which we have reported to be dependent on polyamine synthesis by arginase and ornithine decarboxylase. During metabolic back-conversion, polyamines are oxidized and release H2O2, which can cause apoptosis by mitochondrial membrane depolarization. We hypothesized that this mechanism is induced by H. pylori in macrophages. Polyamine oxidation can occur by acetylation of spermine or spermidine by spermidine/spermine N-1-acetyltransferase prior to back-conversion by acetylpolyamine oxidase, but recently direct conversion of spermine to spermidine by the human polyamine oxidase h1, also called spermine oxidase, has been demonstrated. H. pylori induced expression and activity of the mouse homologue of this enzyme ( polyamine oxidase 1 (PAO1)) by 6 h in parallel with ornithine decarboxylase, consistent with the onset of apoptosis, while spermidine/spermine N-1-acetyltransferase activity was delayed until 18 h when late stage apoptosis had already peaked. Inhibition of PAO1 by MDL 72527 or by PAO1 small interfering RNA significantly attenuated H. pylori-induced apoptosis. Inhibition of PAO1 also significantly reduced H2O2 generation, mitochondrial membrane depolarization, cytochrome c release, and caspase-3 activation. Overexpression of PAO1 by transient transfection induced macrophage apoptosis. The importance of H2O2 was confirmed by inhibition of apoptosis with catalase. These studies demonstrate a new mechanism for pathogen-induced oxidative stress in macrophages in which activation of PAO1 leads to H2O2 release and apoptosis by a mitochondrial-dependent cell death pathway, contributing to deficiencies in host defense in diseases such as H. pylori infection.