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.