Resveratrol decreases the levels of miR-155 by upregulating miR-663, a microRNA targeting JunB and JunD.
An inflammatory component is present in the microenvironment of most neoplastic tissues, including those not causally related to an obvious inflammatory process. Several microRNAs, and especially miR-155, play an essential role in both the innate and adaptative immune response. Resveratrol (trans-3,4',5-trihydroxystilbene) is a natural antioxidant with anti-inflammatory properties that is currently at the stage of preclinical studies for human cancer prevention. Here, we establish that, in human THP-1 monocytic cells as well as in human blood monocytes, resveratrol upregulates miR-663, a microRNA potentially targeting multiple genes implicated in the immune response. In THP-1 cells, miR-663 decreases endogenous activator protein-1 (AP-1) activity and impairs its upregulation by lipopolysaccharides (LPS), at least in part by directly targeting JunB and JunD transcripts. We further establish that the downregulation of AP-1 activity by resveratrol is miR-663 dependent and that the effects of resveratrol on both AP-1 activity and JunB levels are dose dependent. Finally, we show that resveratrol impairs the upregulation of miR-155 by LPS in a miR-663-dependent manner. Given the role of miR-155 in the innate immune response and the fact that it is upregulated in many cancers, our results suggest that manipulating miR-663 levels may help to optimize the use of resveratrol as both an anti-inflammatory and anticancer agent against malignancies associated with high levels of miR-155.
Tili
Esmerina
E
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University, Biomedical Tower, 460 West 12th Avenue, Columbus, OH 43210, USA.
Michaille
Jean-Jacques
JJ
Adair
Brett
B
Alder
Hansjuerg
H
Limagne
Emeric
E
Taccioli
Cristian
C
Ferracin
Manuela
M
Delmas
Dominique
D
Latruffe
Norbert
N
Croce
Carlo M
CM
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008156:Luciferases / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D000077185:Resveratrol; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013267:Stilbenes / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D015854:Up-Regulation
D000972:Antineoplastic Agents, Phytogenic; D014408:Biomarkers, Tumor; D008070:Lipopolysaccharides; C524942:MIRN155 microRNA, human; C552243:MIRN663 microRNA, human; D035683:MicroRNAs; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D013267:Stilbenes; D018808:Transcription Factor AP-1; D008156:Luciferases; D000077185:Resveratrol