title: Oxidized low-density lipoprotein upregulates microRNA-146a via JNK and NF-κB signaling.
abstract: 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.
authors.affiliation: Department of Cardiology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Cardiology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Cardiology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Wenting
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Department of Cardiology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Zewei
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Cardiology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yan
authors.affiliation: Department of Cardiology, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Zhu
mesh_terms: D001483:Base Sequence; D001665:Binding Sites; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D017930:Genes, Reporter; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D051127:Scavenger Receptors, Class E / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D051996:Transcription Factor RelA / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000235:genetics; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D008077:Lipoproteins, LDL; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; C495137:OLR1 protein, human; D051127:Scavenger Receptors, Class E; D018808:Transcription Factor AP-1; D051996:Transcription Factor RelA; C099252:oxidized low density lipoprotein; D048031:JNK Mitogen-Activated Protein Kinases