title: MicroRNA-9 regulates the expression of peroxisome proliferator-activated receptor δ in human monocytes during the inflammatory response.
abstract: PPARδ is involved in the inflammatory response and its expression is induced by cytokines, however, limited knowledge has been produced regarding its regulation. Since recent findings have shown that microRNAs, which are small non-coding RNAs that regulate gene expression, are involved in the immune response, we set out to investigate whether PPARδ can be regulated by microRNAs expressed in monocytes. Bioinformatic analysis identified a putative miR-9 target site within the 3'-UTR of PPARδ that was subsequently verified to be functional using reporter constructs. Primary human monocytes stimulated with LPS showed a downregulation of PPARδ and its target genes after 4 h while the expression of miR-9 was induced. Analysis of pro-inflammatory (M1) and anti-inflammatory (M2) macrophages showed that human PPARδ mRNA as well as miR-9 expression was higher in M1 compared to M2 macrophages. Furthermore, treatment with the PPARδ agonist, GW501516, induced the expression of PPARδ target genes in the pro-inflammatory M1 macrophages while no change was observed in the anti-inflammatory M2 macrophages. Taken together, these data suggest that PPARδ is regulated by miR-9 in monocytes and that activation of PPARδ may be of importance in M1 pro-inflammatory but not in M2 anti-inflammatory macrophages in humans.
authors.affiliation: Atherosclerosis Research Unit, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital L8:03, SE-171 76 Stockholm, Sweden.
authors.forename: Petra
authors.initials: P
authors.lastname: Thulin
authors.forename: Tianling
authors.initials: T
authors.lastname: Wei
authors.forename: Olivera
authors.initials: O
authors.lastname: Werngren
authors.forename: Louisa
authors.initials: L
authors.lastname: Cheung
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Fisher
authors.forename: Dan
authors.initials: D
authors.lastname: Grandér
authors.forename: Martin
authors.initials: M
authors.lastname: Corcoran
authors.forename: Ewa
authors.initials: E
authors.lastname: Ehrenborg
mesh_terms: D001483:Base Sequence; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000473:pathology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D047494:PPAR delta / Q000819:agonists / Q000235:genetics* / Q000378:metabolism; D000070780:Perilipin-2; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: C425931:GW 501516; D008070:Lipopolysaccharides; C541874:MIRN92 microRNA, human; D008565:Membrane Proteins; D035683:MicroRNAs; D047494:PPAR delta; D000070780:Perilipin-2; D012333:RNA, Messenger; D013844:Thiazoles