The deprivation of zinc, caused by malnutrition or as a consequence of aging or disease, strongly affects immune cell functions, causing higher frequency of infections. Among other effects, an increased production of reactive oxygen species (ROS) and proinflammatory cytokines has been observed in zinc-deficient patients, but the underlying mechanisms were unknown. The aim of the current study was to define mechanisms explaining the increase in proinflammatory cytokine production during zinc deficiency, focusing on the role of epigenetic and redox-mediated mechanisms. Interleukin (IL)-1β and tumor necrosis factor (TNF)α production was increased in HL-60 cells under zinc deficiency. Analyses of the chromatin structure demonstrated that the elevated cytokine production was due to increased accessibilities of IL-1β and TNFα promoters in zinc-deficient cells. Moreover, the level of nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) oxidase-produced ROS was elevated under zinc deficiency, subsequently leading to p38 mitogen-activated protein kinase (MAPK) phosphorylation. The increased activation of p38 MAPK appeared to be necessary for posttranscriptional processes in IL-1β and TNFα synthesis. These data demonstrate that IL-1β and TNFα expression under zinc deficiency is regulated via epigenetic and redox-mediated mechanisms. Assuming an important role of zinc in proinflammatory cytokine regulation, this should encourage research in the use of zinc supplementation for treatment of inflammatory diseases.

译文

由于营养不良或由于衰老或疾病而导致的锌剥夺强烈影响免疫细胞功能,导致更高的感染频率。除其他影响外,在缺锌患者中观察到活性氧 (ROS) 和促炎细胞因子的产生增加,但其潜在机制尚不清楚。当前研究的目的是定义解释锌缺乏期间促炎细胞因子产生增加的机制,重点是表观遗传和氧化还原介导机制的作用。缺锌条件下HL-60细胞中白细胞介素 (IL)-1β 和肿瘤坏死因子 (TNF)α 的产生增加。对染色质结构的分析表明,细胞因子产生的增加是由于缺锌细胞中IL-1β 和TNF α 启动子的可及性增加。此外,缺锌条件下烟酰胺腺嘌呤二核苷酸磷酸氧化酶 (NADPH) 氧化酶产生的ROS水平升高,随后导致p38丝裂原活化蛋白激酶 (MAPK) 磷酸化。p38 MAPK的激活增加似乎是IL-1β 和tnf α 合成中的转录后过程所必需的。这些数据证明了在锌缺乏下IL-1β 和tnf α 的表达是通过表观遗传和氧化还原介导的机制来调节的。假设锌的重要作用在促炎细胞因子调节中,这应该鼓励研究使用锌补充剂治疗炎症性疾病。

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