Killing of virulent Mycobacterium tuberculosis by reactive nitrogen intermediates produced by activated murine macrophages.
Killing of virulent Mycobacterium tuberculosis by reactive nitrogen intermediates produced by activated murine macrophages.
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DOI：
10.1084/jem.175.4.1111
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发表时间：
1992-04-01
期刊：
影响因子：
--
通讯作者：
Bloom BR
中科院分区：
文献类型：
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作者：
Chan J;Xing Y;Magliozzo RS;Bloom BR
结核病仍然是世界上发病率和死亡率的主要感染原因之一，但巨噬细胞防御结核分枝杆菌的机制仍然不清楚。这项研究的结果表明，由干扰素γ和脂多糖或肿瘤坏死因子α激活的小鼠巨噬细胞既能抑制又能杀死M。结核在小鼠巨噬细胞系和BALB/c小鼠腹腔巨噬细胞中均可证实的这种抗分枝杆菌作用不依赖于巨噬细胞产生活性氧中间体（ROI）的能力。ROI缺陷的鼠巨噬细胞系D9和其ROI生成的亲本系J774.16在活化后均表达相当的抗分枝杆菌活性。此外，氧自由基清除剂超氧化物歧化酶（SOD），过氧化氢酶，甘露醇，和二氮杂双环辛烷对巨噬细胞的抗分枝杆菌活性没有影响。这些结果与M.结核杆菌对酶促产生的H2 O2的反应表明ROI不太可能显著参与杀死M.结核相反，这些巨噬细胞的抗分枝杆菌活性与诱导L-精氨酸依赖的活性氮中间体（RNI）的产生密切相关。可以参与介导这种抗分枝杆菌功能的效应分子是有毒的RNI，包括NO、NO2和HNO 2，如酸化NO2的杀分枝杆菌作用所证明的。氧自由基清除剂SOD偶然干扰RNI的生产，不能用于区分涉及ROI和RNI的杀细胞机制。总体而言，我们的结果支持了这样的观点：RNI的L-精氨酸依赖性产生是激活的小鼠巨噬细胞中负责杀死和抑制毒性M的主要效应机制。结核
Tuberculosis remains one of the major infectious causes of morbidity and mortality in the world, yet the mechanisms by which macrophages defend against Mycobacterium tuberculosis have remained obscure. Results from this study show that murine macrophages, activated by interferon gamma, and lipopolysaccharide or tumor necrosis factor alpha, both growth inhibit and kill M. tuberculosis. This antimycobacterial effect, demonstrable both in murine macrophage cell lines and in peritoneal macrophages of BALB/c mice, is independent of the macrophage capacity to generate reactive oxygen intermediates (ROI). Both the ROI-deficient murine macrophage cell line D9, and its ROI-generating, parental line J774.16, expressed comparable antimycobacterial activity upon activation. In addition, the oxygen radical scavengers superoxide dismutase (SOD), catalase, mannitol, and diazabicyclooctane had no effect on the antimycobacterial activity of macrophages. These findings, together with the results showing the relative resistance of M. tuberculosis to enzymatically generated H2O2, suggest that ROI are unlikely to be significantly involved in killing M. tuberculosis. In contrast, the antimycobacterial activity of these macrophages strongly correlates with the induction of the L-arginine- dependent generation of reactive nitrogen intermediates (RNI). The effector molecule(s) that could participate in mediating this antimycobacterial function are toxic RNI, including NO, NO2, and HNO2, as demonstrated by the mycobacteriocidal effect of acidified NO2. The oxygen radical scavenger SOD adventitiously perturbs RNI production, and cannot be used to discriminate between cytocidal mechanisms involving ROI and RNI. Overall, our results provide support for the view that the L-arginine-dependent production of RNI is the principal effector mechanism in activated murine macrophages responsible for killing and growth inhibiting virulent M. tuberculosis.