Inhibition of human neutrophil IL-8 production by hydrogen peroxide and dysregulation in chronic granulomatous disease
Inhibition of human neutrophil IL-8 production by hydrogen peroxide and dysregulation in chronic granulomatous disease
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DOI：
10.4049/jimmunol.174.1.411
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发表时间：
2005-01-01
影响因子：
4.4
通讯作者：
Gallin, JI
中科院分区：
文献类型：
--
作者：
Lekstrom-Himes, JA;Kuhns, DB;Gallin, JI
对细菌感染的先天免疫反应包括中性粒细胞趋化和激活，但对炎症的调节尚不清楚。甲酰肽是细菌代谢和线粒体蛋白质生物合成的副产物，可诱导中性粒细胞趋化性、活性氧中间体 (1101) 的产生以及中性粒细胞趋化剂 IL-8 的产生。患有慢性肉芽肿病 (CGD) 的患者表现出 ROI 和过氧化氢生成不足，并且对细菌和真菌病原体敏感，并伴有相关的炎症失调和广泛的肉芽肿形成。我们在这项研究中表明，与正常中性粒细胞相比，在 CGD 细胞中，fMLF 诱导 IL-8 产量增加 2 至 4 倍，并产生持续的 IL-8 mRNA 反应。此外，用过氧化氢酶（H2O2 清除剂）或氯化二亚苯基碘鎓（NADPH 氧化酶抑制剂）处理的正常中性粒细胞表现出与 CGD 中性粒细胞相当的 IL-8 反应。添加过氧化氢或 H2O2 生成系统可抑制 CGD 中性粒细胞中观察到的持续 IL-8 mRNA 和增加的蛋白质产量。这些结果表明，NADPH 氧化酶激活下游的效应子负向调节正常中性粒细胞中的 IL-8 mRNA，而 CGD 细胞中这些效应子的缺失导致 IL-8 mRNA 升高时间延长和 IL-8 水平升高。 ROI 可能在通过这种机制调节炎症方面发挥关键作用。
The innate immune response to bacterial infections includes neutrophil chemotaxis and activation, but regulation of inflammation is less well understood. Formyl peptides, byproducts of bacterial metabolism as well as mitochondrial protein biosynthesis, induce neutrophil chemotaxis, the generation of reactive oxygen intermediates (1101), and the production of the neutrophil chemoattractant, IL-8. Patients with chronic granulomatous disease (CGD) exhibit deficient generation of ROI and hydrogen peroxide and susceptibility to bacterial and fungal pathogens, with associated dysregulated inflammation and widespread granuloma formation. We show in this study that in CGD cells, fMLF induces a 2- to 4-fold increase in IL-8 production and a sustained IL-8 mRNA response compared with normal neutrophils. Moreover, normal neutrophils treated with catalase (H2O2 scavenger) or diphenyleneiodonium chloride (NADPH oxidase inhibitor) exhibit IL-8 responses comparable to those of CGD neutrophils. Addition of hydrogen peroxide or an H2O2-generating system suppresses the sustained IL-8 mRNA and increased protein production observed in CGD neutrophils. These results indicate that effectors downstream of the activation of NADPH oxidase negatively regulate IL-8 mRNA in normal neutrophils, and their absence in CGD cells results in prolonged IL-8 mRNA elevation and enhanced IL-8 levels. ROI may play a critical role in regulating inflammation through this mechanism.