title: Toll-like receptor-4 (TLR4) down-regulates microRNA-107, increasing macrophage adhesion via cyclin-dependent kinase 6.
abstract: Toll-like receptors (TLRs) modulate the expression of multiple microRNAs (miRNAs). Here, we report the down-regulation of miR-107 by TLR4 in multiple cell types. The miR-107 sequence occurs in an intron within the sequence encoding the gene for pantothenate kinase 1α (PanK1α), which is regulated by the transcription factor peroxisome proliferator-activating receptor α (PPAR-α). PanK1α is also decreased in response to lipopolysaccharide (LPS). The effect on both miR-107 and PanK1α is consistent with a decrease in PPAR-α expression. We have found that the putative miR-107 target cyclin-dependent kinase 6 (CDK6) expression is increased by TLR4 as a result of the decrease in miR-107. This effect is required for increased adhesion of macrophages in response to LPS, and CDK6-deficient mice are resistant to the lethal effect of LPS. We have therefore identified a mechanism for LPS signaling which involves a decrease in miR-107 leading to an increase in CDK6.
authors.affiliation: School of Biochemistry and Immunology, Trinity College Dublin, Dublin 2, Ireland.
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Hennessy
authors.forename: Frederick J
authors.initials: FJ
authors.lastname: Sheedy
authors.forename: David
authors.initials: D
authors.lastname: Santamaria
authors.forename: Mariano
authors.initials: M
authors.lastname: Barbacid
authors.forename: Luke A J
authors.initials: LA
authors.lastname: O'Neill
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism*; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043244:Ribonuclease III / Q000378:metabolism; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000172:deficiency / Q000378:metabolism
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008070:Lipopolysaccharides; C549045:MIRN107 microRNA, human; D035683:MicroRNAs; D053594:Myeloid Differentiation Factor 88; D047493:PPAR alpha; D012333:RNA, Messenger; C498144:Rela protein, mouse; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D017853:Phosphotransferases (Alcohol Group Acceptor); C023088:pantothenate kinase; D051361:Cyclin-Dependent Kinase 6; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases