title: MicroRNA-146a-5p Negatively Regulates Pro-Inflammatory Cytokine Secretion and Cell Activation in Lipopolysaccharide Stimulated Human Hepatic Stellate Cells through Inhibition of Toll-Like Receptor 4 Signaling Pathways.
abstract: Lipopolysaccharide (LPS)/toll-like receptor 4 (TLR4) signaling pathway is demonstrated to be involved in the hepatic fibrosis. MicroRNA (miR)-146a-5p is a key regulator of the innate immune response. The functional significance of miR-146a-5p during the LPS/TLR4 mediated hepatic fibrosis process remains unclear. In this study, we found that TLR4 and α-smooth muscle actin (α-SMA) were up-regulated and miR-146a-5p was down-regulated in human hepatic stellate cell (HSC) line LX2 after LPS stimulation. Overexpression of miR-146a-5p inhibited LPS induced pro-inflammatory cytokines secretion through down-regulating the expression levels of TLR-4, IL-1 receptor-associated kinase 1 (IRAK1), TNF receptor associated factor-6 (TRAF6) and phosphorylation of nuclear factor-kappa B (NF-κB). Knockdown of IRAK1 and TRAF6 also suppressed pro-inflammatory cytokine production by inhibiting NF-κB phosphorylation. In addition, miR-146a-5p mimic blocked LPS induced TRAF6 dependent c-Jun N-terminal kinase (JNK) and Smad2 activation as well as α-SMA production. Taken together, these results suggest that miR-146a-5p suppresses pro-inflammatory cytokine secretion and cell activation of HSC through inhibition of TLR4/NF-κB and TLR4/TRAF6/JNK pathway.
authors.affiliation: Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China. cspnr1@126.com.
authors.forename: Yuhan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China. zeng.zhaochong@zs-hospital.sh.cn.
authors.forename: Zhaochong
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China. shen.xiaoyun@zs-hospital.sh.cn.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China. wuzhifeng2@126.com.
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Department of Radiation Oncology, Zhongshan Hospital, Fudan University, Shanghai 200032, China. dongyinyingfd_1@163.com.
authors.forename: Yinying
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Division of Radiation Oncology, Departments of Oncology, National Taiwan University Hospital, Taipei 100, Taiwan. jasoncheng@ntu.edu.tw.
authors.forename: Jason Chia-Hsien
authors.initials: JC
authors.lastname: Cheng
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000070416:Antagomirs / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D048029:TNF Receptor-Associated Factor 6 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C541116:ACTA2 protein, human; D000199:Actins; D000070416:Antagomirs; D016207:Cytokines; D008070:Lipopolysaccharides; D035683:MicroRNAs; D016328:NF-kappa B; D034741:RNA, Small Interfering; D051899:Smad2 Protein; D048029:TNF Receptor-Associated Factor 6; D051197:Toll-Like Receptor 4; D053592:Interleukin-1 Receptor-Associated Kinases; D048031:JNK Mitogen-Activated Protein Kinases
keywords: hepatic fibrosis; inflammation; microRNA-146a; toll like receptor 4