title: Post-transcriptional regulation of cystic fibrosis transmembrane conductance regulator expression and function by microRNAs.
abstract: MicroRNAs (miRNAs) are increasingly recognized as important posttranscriptional regulators of gene expression, and changes in their actions can contribute to disease states. Little is understood regarding miRNA functions in the airway epithelium under normal or diseased conditions. We profiled miRNA expression in well-differentiated primary cultures of human cystic fibrosis (CF) and non-CF airway epithelia, and discovered that miR-509-3p and miR-494 concentrations were increased in CF epithelia. Human non-CF airway epithelia, transfected with the mimics of miR-509-3p or miR-494, showed decreased cystic fibrosis transmembrane conductance regulator (CFTR) expression, whereas their respective anti-miRs exerted the opposite effect. Interestingly, the two miRNAs acted cooperatively in regulating CFTR expression. Upon infecting non-CF airway epithelial cells with Staphylococcus aureus, or upon stimulating them with the proinflammatory cytokines TNF-α or IL-1β, we observed an increased expression of both miRNAs and a concurrent decrease in CFTR expression and function, suggesting that inflammatory mediators may regulate these miRNAs. Transfecting epithelia with anti-miRs for miR-509-3p and miR-494, or inhibiting NF-κB signaling before stimulating cells with TNFα or IL-1β, suppressed these responses, suggesting that the expression of both miRNAs was responsive to NF-κB signaling. Thus, miR-509-3p and miR-494 are dynamic regulators of CFTR abundance and function in normal, non-CF airway epithelia.
authors: 1 Department of Pediatrics.
authors: Shyam
authors: S
authors: Ramachandran
authors: Philip H
authors: PH
authors: Karp
authors: Samantha R
authors: SR
authors: Osterhaus
authors: Peng
authors: P
authors: Jiang
authors: Christine
authors: C
authors: Wohlford-Lenane
authors: Kim A
authors: KA
authors: Lennox
authors: Ashley M
authors: AM
authors: Jacobi
authors: Kal
authors: K
authors: Praekh
authors: Scott D
authors: SD
authors: Rose
authors: Mark A
authors: MA
authors: Behlke
authors: Yi
authors: Y
authors: Xing
authors: Michael J
authors: MJ
authors: Welsh
authors: Paul B
authors: PB
authors: McCray
mesh_terms: D002460:Cell Line; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D012323:RNA Processing, Post-Transcriptional; D020545:Respiratory Mucosa / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: C505032:CFTR protein, human; D018836:Inflammation Mediators; D053583:Interleukin-1beta; C547168:MIRN494 microRNA, human; C571981:MIRN508 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
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