title: miR-146a regulates mechanotransduction and pressure-induced inflammation in small airway epithelium.
abstract: Mechanical ventilation generates biophysical forces, including high transmural pressures, which exacerbate lung inflammation. This study sought to determine whether microRNAs (miRNAs) respond to this mechanical force and play a role in regulating mechanically induced inflammation. Primary human small airway epithelial cells (HSAEpCs) were exposed to 12 h of oscillatory pressure and/or the proinflammatory cytokine TNF-α. Experiments were also conducted after manipulating miRNA expression and silencing the transcription factor NF-κB or toll-like receptor proteins IRAK1 and TRAF6. NF-κB activation, IL-6/IL-8/IL-1β cytokine secretion, miRNA expression, and IRAK1/TRAF6 protein levels were monitored. A total of 12 h of oscillatory pressure and TNF-α resulted in a 5- to 7-fold increase in IL-6/IL-8 cytokine secretion, and oscillatory pressure also resulted in a time-dependent increase in IL-6/IL-8/IL-1β cytokine secretion. Pressure and TNF-α also resulted in distinct patterns of miRNA expression, with miR-146a being the most deregulated miRNA. Manipulating miR-146a expression altered pressure-induced cytokine secretion. Silencing of IRAK1 or TRAF6, confirmed targets of miR-146a, resulted in a 3-fold decrease in pressure-induced cytokine secretion. Cotransfection experiments demonstrate that miR-146a's regulation of pressure-induced cytokine secretion depends on its targeting of both IRAK1 and TRAF6. MiR-146a is a mechanosensitive miRNA that is rapidly up-regulated by oscillatory pressure and plays an important role in regulating mechanically induced inflammation in lung epithelia.
authors.affiliation: Department of Biomedical Engineering, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Huang
authors.forename: Melissa
authors.initials: M
authors.lastname: Crawford
authors.forename: Natalia
authors.initials: N
authors.lastname: Higuita-Castro
authors.forename: Patrick
authors.initials: P
authors.lastname: Nana-Sinkam
authors.forename: Samir N
authors.initials: SN
authors.lastname: Ghadiali
mesh_terms: D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects*; D006801:Humans; D007249:Inflammation / Q000209:etiology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000503:physiopathology*; D040542:Mechanotransduction, Cellular / Q000187:drug effects; D035683:MicroRNAs / Q000096:biosynthesis / Q000502:physiology*; D016328:NF-kappa B / Q000494:pharmacology; D011312:Pressure; D048029:TNF Receptor-Associated Factor 6 / Q000187:drug effects / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016207:Cytokines; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D048029:TNF Receptor-Associated Factor 6; D014409:Tumor Necrosis Factor-alpha; C507768:IRAK1 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases