title: miR-16 targets transcriptional corepressor SMRT and modulates NF-kappaB-regulated transactivation of interleukin-8 gene.
abstract: The signaling pathways associated with the Toll-like receptors (TLRs) and nuclear factor-kappaB (NF-κB) are essential to pro-inflammatory cytokine and chemokine expression, as well as initiating innate epithelial immune responses. The TLR/NF-κB signaling pathways must be stringently controlled through an intricate network of positive and negative regulatory elements. MicroRNAs (miRNAs) are non-coding small RNAs that regulate the stability and/or translation of protein-coding mRNAs. Herein we report that miR-16 promotes NF-κB-regulated transactivation of the IL-8 gene by suppression of the silencing mediator for retinoid and thyroid hormone receptor (SMRT). LPS stimulation activated miR-16 gene transcription in human monocytes (U937) and biliary epithelial cells (H69) through MAPK-dependent mechanisms. Transfection of cells with the miR-16 precursor promoted LPS-induced production of IL-8, IL-6, and IL-1α, without a significant effect on their RNA stability. Instead, an increase in NF-κB-regulated transactivation of the IL-8 gene was confirmed in cells following transfection of miR-16 precursor. Importantly, miR-16 targeted the 3'-untranslated region of SMRT and caused translational suppression of SMRT. LPS decreased SMRT expression via upregulation of miR-16. Moreover, functional manipulation of SMRT altered NF-κB-regulated transactivation of LPS-induced IL-8 expression. These data suggest that miR-16 targets SMRT and modulates NF-κB-regulated transactivation of the IL-8 gene.
authors.affiliation: Department of Medical Microbiology and Immunology, Creighton University Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhou
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Li
authors.forename: Guoku
authors.initials: G
authors.lastname: Hu
authors.forename: Ai-Yu
authors.initials: AY
authors.lastname: Gong
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Drescher
authors.forename: Xian-Ming
authors.initials: XM
authors.lastname: Chen
mesh_terms: D000873:Anthracenes / Q000494:pharmacology; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005419:Flavonoids / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016209:Interleukin-8 / Q000235:genetics* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D056985:Nuclear Receptor Co-Repressor 2 / Q000235:genetics* / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000235:genetics; D020298:U937 Cells
chemical_list: D000873:Anthracenes; C508606:CXCL8 protein, human; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D016209:Interleukin-8; D008070:Lipopolysaccharides; C505362:MIRN16 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D056985:Nuclear Receptor Co-Repressor 2; D011725:Pyridines; C432165:pyrazolanthrone; D048049:Extracellular Signal-Regulated MAP Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one