MicroRNA-674-5p/5-LO axis involved in autoimmune reaction of Concanavalin A-induced acute mouse liver injury

• Published in: Toxicology letters Vol. 258; pp. 101 - 107
• Main Authors: Su, Kunkai, Wang, Qi, Qi, Luoyang, Hua, Dasong, Tao, Jingjing, Mangan, Connor J., Lou, Yijia, Li, Lanjuan
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 06.09.2016
• Subjects: 5-lipoxygenase; Animals; Arachidonate 5-Lipoxygenase - chemistry; Arachidonate 5-Lipoxygenase - genetics; Arachidonate 5-Lipoxygenase - metabolism; Arachidonic acid; Attenuation; Biotechnology; Cell Line; Concanavalin A; Control; Disease Models, Animal; Enzyme Induction - drug effects; Gene Expression Profiling; Gene Expression Regulation - drug effects; Hepatitis, Autoimmune - drug therapy; Hepatitis, Autoimmune - immunology; Hepatitis, Autoimmune - metabolism; Hepatitis, Autoimmune - pathology; Hepatotoxicity; Humans; Immunosuppressive Agents - pharmacology; Injuries; Interleukin-6 - metabolism; Leukotrienes - metabolism; Liver; Liver - drug effects; Liver - immunology; Liver - metabolism; Liver - pathology; Male; Mice; Mice, Inbred BALB C; MicroRNAs - antagonists & inhibitors; MicroRNAs - metabolism; miR-674-5p; Pathways; Regulators; Specific Pathogen-Free Organisms; Tumor Necrosis Factor-alpha - metabolism; miR-674-5p; 5-lipoxygenase; Concanavalin A; Hepatotoxicity
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/j.toxlet.2016.06.010

•Cysteinyl-leukotrienes accumulated during Concanavalin A-induced mouse liver injury.•5-LO upregulation triggered the autoimmune reaction after Concanavalin A challenge.•Seven upregulated and two downregulated miRs were found related to hepatotoxicity of Concanavalin A.•MiR-674-5p negatively regulated 5-LO in hepatic cells with IL-6 or TNF-α presence. Autoimmune hepatitis is characterized, in part, by the pathways involving cysteinyl-leukotriene metabolites of arachidonic acid, the dynamics of which remain unclear. Here, we explored post-transcriptional regulation in the 5-lipoxygenase (5-LO) pathway of arachidonic acid in a Concanavalin A (Con A) induced mouse model. We found that Con A administration lead to 5-LO overexpression and cysteinyl-leukotriene release in early hepatic injury, which was attenuated by cyclosporin A pretreatment. Subsequent microarray and qRT-PCR analysis further showed that microRNA-674-5p (miR-674-5p) displayed a significant decrease in expression in Con A-damaged liver. Noting that miR-674-5p harbors a potential binding region for 5-LO, we further transfected hepatic cell lines with overexpressing miR-674-5p mimic and discovered a negative regulating effect of miR-674-5p on 5-LO expression in the presence of IL-6 or TNF-α. These findings suggest that miR-674-5p might be a negative regulator in 5-LO mediated autoimmune liver injury, representing a compelling avenue towards future therapeutic interventions.