MicroRNA-155 Silencing Enhances Inflammatory Response and Lipid Uptake in Oxidized Low-Density Lipoprotein-Stimulated Human THP-1 Macrophages

• Published in: Journal of investigative medicine 2010-12, Vol.58 (8), p.961-967
• Main Authors: Huang, Ri-sheng, Hu, Guan-qiong, Lin, Bin, Lin, Zhi-yi, Sun, Cheng-chao
• Format: Article
• Language: English
• Subjects: Blotting, Western; Cell Line, Tumor; Chromatography, High Pressure Liquid; Cytokines - metabolism; Dose-Response Relationship, Drug; Gene Expression Regulation - drug effects; Gene Knockdown Techniques; Gene Silencing - drug effects; Humans; Inflammation - chemically induced; Inflammation - genetics; Inflammation - metabolism; Lipid Metabolism - drug effects; Lipoproteins, LDL - pharmacology; Macrophages - drug effects; Macrophages - metabolism; MicroRNAs - genetics; Transfection
• ISSN: 1081-5589; 1708-8267
• DOI: 10.2310/JIM.0b013e3181ff46d7

It has been proposed that the inflammatory response of monocytes/macrophages induced by oxidized low-density lipoprotein (oxLDL) is a key event in the pathogenesis of atherosclerosis. MicroRNA-155 (miR-155) is an important regulator of the immune system and has been shown to be involved in acute inflammatory response. However, the function of miR-155 in oxLDL-stimulated inflammation and atherosclerosis remains unclear. Here, we show that the exposure of human THP-1 macrophages to oxLDL led to a marked up-regulation of miR-155 in a dose-dependent manner. Silencing of endogenous miR-155 in THP-1 cells using locked nucleic acid-modified antisense oligonucleotides significantly enhanced oxLDL-induced lipid uptake, up-regulated the expression of scavenger receptors (lectinlike oxidized LDL receptor-1, cluster of differentiation 36 [CD36], and CD68), and promoted the release of several cytokines including interleukin (IL)-6, -8, and tumor necrosis factor α (TNF-α). Luciferase reporter assay showed that targeting miR-155 promoted nuclear factor-kappa B (NF-κB) nuclear translocation and potentiated the NF-κB-driven transcription activity. Moreover, miR-155 knockdown resulted in a marked increase in the protein amount of myeloid differentiation primary response gene 88 (MyD88), an important adapter protein used by Toll-like receptors to activate the NF-κB pathway. Our data demonstrate that miR-155 serves as a negative feedback regulator in oxLDL-stimulated THP-1 inflammatory responses and lipid uptake and thus might have potential therapeutic implications in atherosclerosis.