miR-146a ameliorates liver ischemia/reperfusion injury by suppressing IRAK1 and TRAF6

• Published in: PloS one Vol. 9; no. 7; p. e101530
• Main Authors: Jiang, Weiwei, Kong, Liangliang, Ni, Qingfeng, Lu, Yeting, Ding, Wenzhou, Liu, Guoqing, Pu, Liyong, Tang, Weibing, Kong, Lianbao
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 02.07.2014; Public Library of Science (PLoS)
• Subjects: Animals; Apoptosis; Biology and life sciences; Cell culture; Cell Hypoxia; Cell Line; Cytokines; Deactivation; Down-Regulation; Gene expression; Hepatic Insufficiency - genetics; Hepatic Insufficiency - immunology; Hepatic Insufficiency - pathology; Hepatocytes; Hypoxia; Immune system; Immunology; Inactivation; Inflammation; Inflammation - genetics; Inflammation - immunology; Inflammation - pathology; Injuries; Interleukin 1; Interleukin 1 receptors; Interleukin-1 Receptor-Associated Kinases - genetics; Interleukin-1 Receptor-Associated Kinases - immunology; IRAK protein; Ischemia; Kinases; Kupffer cells; Laboratory animals; Liver; Liver - immunology; Liver - metabolism; Liver - pathology; Macrophages; Macrophages - immunology; Macrophages - metabolism; Macrophages - pathology; Male; Medical research; Mice; Mice, Inbred C57BL; MicroRNA; MicroRNAs; MicroRNAs - genetics; MicroRNAs - immunology; miRNA; NF-κB protein; Pathogenesis; Penicillin; Physiology; Proteins; Reperfusion; Reperfusion Injury - genetics; Reperfusion Injury - immunology; Reperfusion Injury - pathology; Research and Analysis Methods; Ribonucleic acid; RNA; Rodents; Signal Transduction; Signaling; Surgery; TNF Receptor-Associated Factor 6 - genetics; TNF Receptor-Associated Factor 6 - immunology; Toll-like receptors; Toll-Like Receptors - immunology; TRAF6 protein; Transplants & implants; Tumor necrosis factor; Tumor necrosis factor-TNF; United States > US; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0101530

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.