Helicobacter pylori induces macrophage apoptosis by activation of arginase II
Helicobacter pylori induces macrophage apoptosis by activation of arginase II
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DOI：
10.4049/jimmunol.168.9.4692
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发表时间：
2002-05-01
影响因子：
4.4
通讯作者：
Wilson, KT
中科院分区：
文献类型：
--
作者：
Gobert, AP;Cheng, YL;Wilson, KT
幽门螺杆菌感染诱导巨噬细胞的先天性免疫应答，导致粘膜炎症和损伤。巨噬细胞凋亡在粘膜感染的发病机制中是重要的，但尚未用H.幽门。诱导型一氧化氮合酶（inducible NO synthase，iNOS）产生的一氧化氮（NO）可激活巨噬细胞凋亡。精氨酸酶通过将L-精氨酸转化为L-鸟氨酸而与iNOS竞争。自从我们报道H. pylori诱导巨噬细胞中的iNOS，我们现在确定该细菌是否诱导凋亡酶以及这种激活对细胞凋亡的影响。在与H.幽门。细胞凋亡的时间过程相匹配的酶和iNOS活性。令人惊讶的是，细胞凋亡被腺苷酸酶抑制剂N-ω-羟基-L-精氨酸或N-ω-羟基-去甲-L-精氨酸阻断，但不被iNOS抑制剂N-亚氨基乙基-L-赖氨酸阻断。这些发现在iNOS缺陷小鼠的腹腔巨噬细胞中得到证实，并且不依赖于细菌-巨噬细胞接触。在H.幽门刺激的巨噬细胞。细胞凋亡被ODC的抑制所消除，并被多胺、精脒和精胺所恢复。我们还证明，在小鼠和人H. pylori胃炎组织，表明我们的发现可能与体内相关。因此，我们描述了精氨酸酶和ODC依赖性巨噬细胞凋亡，这表明多胺与H.幽门感染
Helicobacter pylori infection induces innate immune responses in macrophages, contributing to mucosal inflammation and damage. Macrophage apoptosis is important in the pathogenesis of mucosal infections but has not been studied with H. pylori. NO derived from inducible NO synthase (iNOS) can activate macrophage apoptosis. Arginase competes with iNOS by converting L-arginine to L-ornithine. Since we reported that H. pylori induces iNOS in macrophages, we now determined whether this bacterium induces arginase and the effect of this activation on apoptosis. NF-kappaB-dependent induction of arginase II, but not arginase I, was observed in RAW 264.7 macrophages cocultured with H. pylori. The time course of apoptosis matched those of both arginase and iNOS activities. Surprisingly, apoptosis was blocked by the arginase inhibitors N-omega-hydroxy-L-arginine or N-omega-hydroxy-nor-L-arginine, but not by the iNOS inhibitor N-iminoethyl-L-lysine. These findings were confirmed in peritoneal macrophages from iNOS-deficient mice and were not dependent on bacterial-macrophage contact. Ornithine decarboxylase (ODC), which metabolizes L-ornithine to polyamines, was also induced in H. pylori-stimulated macrophages. Apoptosis was abolished by inhibition of ODC and was restored by the polyamines spermidine and spermine. We also demonstrate that arginase II expression is up-regulated in both murine and human H. pylori gastritis tissues, indicating the likely in vivo relevance of our findings. Therefore, we describe arginase- and ODC-dependent macrophage apoptosis, which implicates polyamines in the pathophysiology of H. pylori infection.