title: MicroRNA-mediated Th2 bias in methimazole-induced acute liver injury in mice.
abstract: MicroRNA (miRNA) is a class of small non-coding RNAs containing approximately 20 nucleotides that negatively regulate target gene expression. Little is known about the role of individual miRNAs and their targets in immune- and inflammation-related responses in drug-induced liver injury. In the present study, involvement of miRNAs in the T helper (Th) 2-type immune response was investigated using a methimazole (MTZ)-induced liver injury mouse model. Co-administration of L-buthionine-S,R-sulfoximine and MTZ induced acute hepatocellular necrosis and elevated plasma levels of alanine aminotransferase (ALT) from 4h onward in female Balb/c mice. The hepatic mRNA expression of Th2 promotive factors was significantly increased concomitantly with plasma ALT levels. In contrast, the hepatic mRNA expression of Th2 suppressive factors was significantly decreased during the early phase of liver injury. Comprehensive profiling of hepatic miRNA expression was analyzed before the onset of MTZ-induced liver injury. Using in silico prediction of miRNAs that possibly regulate Th2-related genes and subsequent quantification, we identified up-regulation of expression of miR-29b-1-5p and miR-449a-5p. Among targets of these miRNAs, down-regulation of Th2 suppressive transcription factors, such as SRY-related HMG-box 4 (SOX4) and lymphoid enhancer factor-1 (LEF1), were observed from the early phase of liver injury. In conclusion, negative regulation of the expression of SOX4 by miR-29b-1-5p and that of LEF1 by miR-449a-5p is suggested to play an important role in the development of Th2 bias in MTZ-induced liver injury.
authors.affiliation: Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 1-98 Kasugade-naka, 3-chome, Konohana-ku, Osaka, Japan. Electronic address: yasuaki-uematsu@ds-pharma.co.jp.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Uematsu
authors.affiliation: Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Akai
authors.affiliation: Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 1-98 Kasugade-naka, 3-chome, Konohana-ku, Osaka, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Tochitani
authors.affiliation: Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Oda
authors.affiliation: Preclinical Research Laboratories, Sumitomo Dainippon Pharma Co., Ltd., 1-98 Kasugade-naka, 3-chome, Konohana-ku, Osaka, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Yamada
authors.affiliation: Department of Drug Safety Sciences, Division of Clinical Pharmacology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yokoi
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005978:Glutathione / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics; D008713:Methimazole; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000378:metabolism*; D055751:SOXC Transcription Factors / Q000235:genetics; D018418:Th2 Cells / Q000378:metabolism*
chemical_list: C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D035683:MicroRNAs; D055751:SOXC Transcription Factors; C489990:Sox4 protein, mouse; D008713:Methimazole; D000410:Alanine Transaminase; D005978:Glutathione
keywords: Drug-induced liver injury; Methimazole; Mouse; T helper 2; miR-29b-1-5p; miR-449a-5p