Open AccessOxidized low-density lipoprotein upregulates microRNA-146a via JNK and NF-κB signaling
Author(s) -
Zhenwei Li,
Shuai Wang,
Wenting Zhao,
Zewei Sun,
Hui Yan,
Jianhua Zhu
Publication year - 2015
Publication title -
molecular medicine reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.727
H-Index - 56
eISSN - 1791-3004
pISSN - 1791-2997
DOI - 10.3892/mmr.2015.4729
Subject(s) - chromatin immunoprecipitation , microrna , small interfering rna , nf κb , signal transduction , transcription factor , oncogene , microbiology and biotechnology , scavenger receptor , cancer research , biology , chemistry , apoptosis , cell cycle , lipoprotein , promoter , gene expression , transfection , gene , biochemistry , cholesterol
Increasing evidence suggested the involvement of microRNA (miR)-146a in the pathogenesis of multiple diseases, including atherosclerosis, bacterial infection and cancer. However, the mechanism by which miR-146a is regulated in macrophages exposed to oxidized low-density lipoprotein (oxLDL) has remained elusive. The present study aimed to explore the molecular pathway of miR-146a regulation in response to oxLDL. Human THP-1 macrophages were pre-treated with small interfering RNA specific for scavenger receptors or with pharmacological inhibitors prior to oxLDL administration. A filter plate screening assay was performed to identify oxLDL-inducible transcription factors that bind to the miR-146a promoter. The exact binding sites were mapped by chromatin immunoprecipitation. The effects of miR-146a on markers of macrophage maturation were studied by flow cytometry. The results revealed that miR-146a expression was deceased when c-jun N-terminal kinase (JNK) or nuclear factor (NF)-κB signaling was inhibited. By forming a complex with c-jun, which was promoted by oxLDL, the NF-κB sub-unit p65 facilitated the binding of c-jun to the miR-146a promoter to trigger transcriptional activation. miR-146a negatively regulated macrophage maturation by reducing the expression of CD86 and CD80. The present study demonstrated that oxLDL positively regulates miR-146a via the JNK and NF-κB pathways in macrophages, and that miR-146a inhibits inflammatory activation.