Indoxyl sulfate (IS), a uremic toxin, is a sulfate-conjugated metabolite originated from tryptophan. Accumulating uremic toxins may worsen renal diseases and further complicate related disorders including impaired immune functions under oxidative stress conditions. However, it has remained unclear whether or not IS can directly cause the cellular immune dysfunction. We investigated the effects of IS on the intracellular oxidation level and phagocytic activity in a HL-60-differantiated human macrophage cell model. Incubation of the cells in the presence of IS resulted in increasing intracellular oxidation level and decreasing phagocytic activity. In addition to inhibitors for NADH oxidase (NOX), organic anion transporting polypeptide2B1 (OATP2B1), protein kinase C (PKC), and phosphoinositide 3-kinase (PI3K), a representative antioxidant Trolox, was also shown to significantly relieve the IS-induced oxidation and restore weakened phagocytosis. Collectively, IS may directly down-regulate the phagocytic immune function of macrophages through the oxidation mechanisms including OATP2B1, PKC, PI3K, and NOX pathways. Abbreviations: CKD: Chronic kidney disease; IS: Indoxyl sulfate; ROS: Reactive oxygen species; NOX: NADH oxidase; OATP2B1: Organic anion transporting polypeptide2B1; PKC: Protein kinase C; PI3K: Phosphoinositide 3-kinase; 2-APT: 2-acetylphenothiazine.

中文翻译：

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使用HL-60分化的人类巨噬细胞模型研究尿毒症毒素吲哚酚硫酸盐对细胞内氧化水平和吞噬活性的影响。

硫酸吲哚酚（IS）是一种尿毒症毒素，是一种源自色氨酸的硫酸盐结合代谢物。尿毒症毒素的积累可能会使肾脏疾病恶化，并使相关疾病更加复杂，包括在氧化应激条件下免疫功能受损。但是，尚不清楚IS是否可以直接引起细胞免疫功能障碍。我们调查了IS对HL-60分化的人类巨噬细胞模型中细胞内氧化水平和吞噬活性的影响。在IS存在下孵育细胞会导致细胞内氧化水平升高和吞噬活性降低。除了NADH氧化酶（NOX）抑制剂，有机阴离子转运多肽2B1（OATP2B1），蛋白激酶C（PKC）和磷酸肌醇3激酶（PI3K）（代表性的抗氧化剂Trolox）外，还显示出可显着缓解IS诱导的氧化并恢复减弱的吞噬作用。总之，IS可能通过包括OATP2B1，PKC，PI3K和NOX途径在内的氧化机制直接下调巨噬细胞的吞噬免疫功能。缩写：CKD：慢性肾脏病；IS：硫酸吲哚酚；ROS：活性氧；NOX：NADH氧化酶；OATP2B1：有机阴离子转运多肽2B1；PKC：蛋白激酶C；PI3K：磷酸肌醇3-激酶；2-APT：2-乙酰吩噻嗪。活性氧；NOX：NADH氧化酶；OATP2B1：有机阴离子转运多肽2B1；PKC：蛋白激酶C；PI3K：磷酸肌醇3-激酶；2-APT：2-乙酰吩噻嗪。活性氧；NOX：NADH氧化酶；OATP2B1：有机阴离子转运多肽2B1；PKC：蛋白激酶C；PI3K：磷酸肌醇3-激酶；2-APT：2-乙酰吩噻嗪。