title: MicroRNA-146a is upregulated by and negatively regulates TLR2 signaling.
abstract: TLR signaling is a crucial component of the innate immune response to infection. MicroRNAs (miRNAs) have been shown to be upregulated during TLR signaling. Specifically, microRNA-146a (miR-146a) plays a key role in endotoxin tolerance by downregulating interleukin-1 receptor-associated kinase 1 (IRAK-1). The aim of this study was to assess the role of miR-146a in the TLR2 signaling and development of bacterial lipoprotein (BLP) self-tolerance and cross-tolerance to bacteria. Expression of miR-146a increased in a dose- and time-dependent manner in BLP-stimulated human THP-1 promonocytic cells. In BLP-tolerised cells miR-146a was even further upregulated in response to BLP re-stimulation (p<0.001). Re-stimulation of BLP-tolerised cells with heat-killed gram-negative Salmonella typhimurium (S. typhimurium), but not gram-positive Staphylococcus aureus (S. aureus), led to significant overexpression of miR-146a (p<0.05). Transfection of naive cells with a miR-146a mimic substantially suppressed TNF-α production (p<0.05). Furthermore, overexpression of miR-146a resulted in strong reduction in IRAK-1 and phosphorylated IκBα expression in naive and S. typhimurium-stimulated THP-1 cells. Collectively, miR-146a is upregulated in response to BLP and bacterial stimulation in both naive and BLP-tolerised cells. Overexpression of miR-146a induces a state analogous to tolerance in BLP-stimulated cells and therefore may represent a future target for exogenous modulation of tolerance during microbial infection and sepsis.
authors: Department of Academic Surgery, University College Cork, Cork University Hospital, Cork, Ireland.
authors: Edel M
authors: EM
authors: Quinn
authors: Jiang Huai
authors: JH
authors: Wang
authors: Grace
authors: G
authors: O'Callaghan
authors: H Paul
authors: HP
authors: Redmond
mesh_terms: D001426:Bacterial Proteins / Q000494:pharmacology; D002460:Cell Line; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D053592:Interleukin-1 Receptor-Associated Kinases / Q000378:metabolism; D008074:Lipoproteins / Q000494:pharmacology; D035683:MicroRNAs / Q000235:genetics*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000382:microbiology; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D001426:Bacterial Proteins; D008074:Lipoproteins; C542542:MIRN146 microRNA, human; D035683:MicroRNAs; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D053592:Interleukin-1 Receptor-Associated Kinases; D051550:I-kappa B Kinase
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