Department of Pathophysiology, Shaoyang University, Shaoyang, Hunan 422000, China.
The Clinic Medical College, Guilin Medical University, No. 1 Zhiyuan Road, Guilin, Guangxi 541100, China.
Cytokine. 2019 Oct;122:154385. doi: 10.1016/j.cyto.2018.04.028. Epub 2018 Apr 24.
Previous studies suggest that IL-8 has an important role in the regulation of cholesterol efflux, but whether miRNAs are involved in this process is still unknown. The purpose of this study is to explore whether IL-8 promotes cholesterol accumulation by enhancing miR-183 expression in macrophages and its underlying mechanism.
Treatment of THP-1 macrophage-derived foam cells with IL-8 decreased ABCA1 expression and cholesterol efflux. Using bioinformatics analyses and dual-luciferase reporter assays, we found that miR-183 was highly conserved during evolution and directly inhibited ABCA1 protein and mRNA expression by targeting ABCA1 3'UTR. MiR-183 directly regulated endogenous ABCA1 expression levels. Furthermore, IL-8 enhanced the expression of miR-183 and decrease ABCA1 expression. Cholesterol transport assays confirmed that IL-8 dramatically inhibited apolipoprotein AI-mediated ABCA1-dependent cholesterol efflux by increasing miR-183 expression. In contrast, treatment with anti-IL-8 antibody reversed these effects.
IL-8 enhances the expression of miR-183, which then inhibits ABCA1 expression and cholesterol efflux. Our studies suggest that the IL-8-miR-183-ABCA1 axis may play an intermediary role in the development of atherosclerosis.
先前的研究表明，IL-8 在胆固醇外排的调节中具有重要作用，但 miRNA 是否参与这一过程尚不清楚。本研究旨在探讨 IL-8 是否通过增强巨噬细胞中 miR-183 的表达来促进胆固醇积累及其潜在机制。
用 IL-8 处理 THP-1 巨噬细胞源性泡沫细胞可降低 ABCA1 的表达和胆固醇外排。通过生物信息学分析和双荧光素酶报告基因检测，我们发现 miR-183 在进化过程中高度保守，可通过靶向 ABCA1 3'UTR 直接抑制 ABCA1 蛋白和 mRNA 的表达。miR-183 直接调节内源性 ABCA1 的表达水平。此外，IL-8 增强了 miR-183 的表达并降低了 ABCA1 的表达。胆固醇转运实验证实，IL-8 通过增加 miR-183 的表达显著抑制载脂蛋白 AI 介导的 ABCA1 依赖性胆固醇外排。相比之下，用抗 IL-8 抗体处理可逆转这些效应。
IL-8 增强了 miR-183 的表达，进而抑制 ABCA1 的表达和胆固醇外排。我们的研究表明，IL-8-miR-183-ABCA1 轴可能在动脉粥样硬化的发生发展中起中介作用。
