title: miR-146a ameliorates liver ischemia/reperfusion injury by suppressing IRAK1 and TRAF6.
abstract: A critical role of the Toll-like receptor(TLR) and its downstream molecules, including IL-1 receptor-associated kinase 1(IRAK1) and tumor necrosis factor receptor- associated factor 6(TRAF6), in the pathogenesis of liver ischemia/reperfusion (I/R) injury has been documented. Recently a microRNA, miR-146a, was identified as a potent negative regulator of the TLR signaling pathway. In this study, we investigated the role of miR-146a to attenuate TLR signaling and liver I/R injury in vivo and in vitro. miR-146a was decreased in mice Kupffer cells following hepatic I/R, whereas IRAK1 and TRAF6 increased. Overexpression of miR-146a directly decreased IRAK1 and TRAF6 expression and attenuated the release of proinflammatory cytokines through the inactivation of NF-κB P65 in hypoxia/reoxygenation (H/R)-induced macrophages, RAW264.7 cells. Knockdown experiments demonstrated that IRAK1 and TRAF6 are two potential targets for reducing the release of proinflammatory cytokines. Moreover, co-culture assays indicated that miR-146a decreases the apoptosis of hepatocytes after H/R. In vivo administration of Ago-miR-146a, a stable version of miR-146a in vivo, protected against liver injury in mice after I/R via inactivation of the TLR signaling pathway. We conclude that miR-146a ameliorates liver ischemia/reperfusion injury in vivo and hypoxia/reoxygenation injury in vitro by directly suppressing IRAK1 and TRAF6.
authors.affiliation: Department of Neonatal Surgery, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing, China.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Jiang
authors.affiliation: Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Liangliang
authors.initials: L
authors.lastname: Kong
authors.affiliation: Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Qingfeng
authors.initials: Q
authors.lastname: Ni
authors.affiliation: Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Yeting
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Wenzhou
authors.initials: W
authors.lastname: Ding
authors.affiliation: Department of Neonatal Surgery, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing, China.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Liyong
authors.initials: L
authors.lastname: Pu
authors.affiliation: Department of Neonatal Surgery, Nanjing Children's Hospital Affiliated to Nanjing Medical University, Nanjing, China.
authors.forename: Weibing
authors.initials: W
authors.lastname: Tang
authors.affiliation: Department of Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Lianbao
authors.initials: L
authors.lastname: Kong
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D002460:Cell Line; D015536:Down-Regulation; D048550:Hepatic Insufficiency / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics* / Q000276:immunology; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000276:immunology; D015427:Reperfusion Injury / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics* / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology
chemical_list: D035683:MicroRNAs; C534190:Mirn146 microRNA, mouse; D048029:TNF Receptor-Associated Factor 6; D051193:Toll-Like Receptors; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse