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首页> 外文期刊>Immunology: An Official Journal of the British Society for Immunology >Adenanthin, a new inhibitor of thiol-dependent antioxidant enzymes, impairs the effector functions of human natural killer cells
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Adenanthin, a new inhibitor of thiol-dependent antioxidant enzymes, impairs the effector functions of human natural killer cells

机译：腺嘌呤，一种新的硫醇依赖性抗氧化酶抑制剂，会损害人类自然杀伤细胞的效应子功能

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Natural killer (NK) cells are considered critical components of the innate and adaptive immune responses. Deficiencies in NK cell activity are common, such as those that occur in cancer patients, and they can be responsible for dysfunctional immune surveillance. Persistent oxidative stress is intrinsic to many malignant tumours, and numerous studies have focused on the effects of reactive oxygen species on the anti-tumour activity of NK cells. Indeed, investigations in animal models have suggested that one of the most important thiol-dependent antioxidant enzymes, peroxiredoxin1 (PRDX1), is essential for NK cell function. In this work, our analysis of the transcriptomic expression pattern of antioxidant enzymes in human NK cells has identified PRDX1 as the most prominently induced transcript out of the 18 transcripts evaluated in activated NK cells. The change in PRDX1 expression was followed by increased expression of two other enzymes from the PRDX-related antioxidant chain: thioredoxin and thioredoxin reductase. To study the role of thiol-dependent antioxidants in more detail, we applied a novel compound, adenanthin, to induce an abrupt dysfunction of the PRDX-related antioxidant chain in NK cells. In human primary NK cells, we observed profound alterations in spontaneous and antibody-dependent NK cell cytotoxicity against cancer cells, impaired degranulation, and a decreased expression of activation markers under these conditions. Collectively, our study pinpoints the unique role for the antioxidant activity of the PRDX-related enzymatic chain in human NK cell functions. Further understanding this phenomenon will prospectively lead to fine-tuning of the novel NK-targeted therapeutic approaches to human disease.
机译：自然杀伤（NK）细胞被认为是先天和适应性免疫反应的关键组成部分。 NK细胞活性不足是常见的，例如发生在癌症患者中的那些，它们可能是免疫监控功能失调的原因。持久性氧化应激是许多恶性肿瘤所固有的，许多研究集中于活性氧对NK细胞抗肿瘤活性的影响。实际上，在动物模型中的研究表明，最重要的硫醇依赖性抗氧化酶之一过氧化物irexin1（PRDX1）对NK细胞功能至关重要。在这项工作中，我们对人类NK细胞中抗氧化酶的转录组表达模式的分析已将PRDX1确定为在活化的NK细胞中评估的18种转录物中最突出的诱导转录本。 PRDX1表达的变化之后，来自PRDX相关抗氧化剂链的另外两种酶（硫氧还蛋白和硫氧还蛋白还原酶）的表达增加。为了更详细地研究硫醇依赖性抗氧化剂的作用，我们应用了一种新型化合物腺嘌呤，以诱导NK细胞中PRDX相关抗氧化剂链的突然功能障碍。在人类原代NK细胞中，我们观察到在这些条件下，自发和抗体依赖性NK细胞对癌细胞的细胞毒性发生了深刻变化，脱粒受损，激活标记的表达降低。总之，我们的研究指出了PRDX相关酶链的抗氧化活性在人类NK细胞功能中的独特作用。进一步了解这种现象将有望导致针对人类疾病的新型针对NK的治疗方法的微调。

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