title: MiR-221 activates the NF-κB pathway by targeting A20.
abstract: MicroRNAs play an important role in regulating the inflammatory response, and are critically involved in the development of inflammatory disorders, including those affecting the lungs. While the microRNA miR-221 is involved in embryonic lung branching morphogenesis and epithelial cell development, its importance in lung inflammation has not been previously explored. In our current study, expression of miR-221 was selectively decreased by exposure to lipopolysaccharides (LPS) both in vitro and in vivo. Enforced expression of miR-221 significantly increased the production of proinflammatory cytokines TNF-α and IL-6, and enhanced the activation of NF-κB and MAPKs upon LPS stimulation. Accordingly, intratracheal stimulation of miR-221 was shown to aggravate endotoxin-induced acute lung injuries and inflammation in mice. Mechanistic studies showed that miR-221 directly targets A20, a master regulator of NF-κB and MAPK signaling, and thus represses inflammatory signaling. Restoration of A20 in macrophages abolished the stimulatory effect of miR-221 on production of proinflammatory cytokines. Together, these results indicate the presence of a novel miRNA-mediated feed-back mechanism that controls inflammation, and suggest involvement of aberrant miR-221 expression in the development of inflammatory lung disorders.
authors.affiliation: Department of Basic Medical Science, Key Laboratory of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China. Electronic address: zdj2010@hznu.edu.cn.
authors.forename: Dongjiu
authors.initials: D
authors.lastname: Zhao
authors.affiliation: Department of Basic Medical Science, Key Laboratory of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China. Electronic address: zhuangz254@163.com.
authors.forename: Ningtong
authors.initials: N
authors.lastname: Zhuang
authors.affiliation: Department of Basic Medical Science, Key Laboratory of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China. Electronic address: Dina_you11@163.com.
authors.forename: Yina
authors.initials: Y
authors.lastname: Ding
authors.affiliation: Department of Basic Medical Science, Key Laboratory of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China. Electronic address: 13758140215@163.com.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Kang
authors.affiliation: Department of Basic Medical Science, Key Laboratory of Immunology and Molecular Medicine, School of Medicine, Hangzhou Normal University, Hangzhou, Zhejiang 310036, China. Electronic address: shi_liyun01@163.com.
authors.forename: Liyun
authors.initials: L
authors.lastname: Shi
mesh_terms: D055371:Acute Lung Injury / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D018836:Inflammation Mediators / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D000067996:RAW 264.7 Cells; D015398:Signal Transduction / Q000187:drug effects; D051193:Toll-Like Receptors / Q000378:metabolism; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; C546122:MIRN221 microRNA, mouse; D035683:MicroRNAs; D016328:NF-kappa B; D051193:Toll-Like Receptors; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse
keywords: A20; Inflammation; miR-221