Drug-induced liver injury (DILI) is a serious problem in pre-clinical stages of drug development and clinical pharmacotherapy, but the pathogenesis of DILI has not been elucidated. Flucloxacillin (FLX), which is a β-lactam antibiotic of the penicillin class that is used widely in Europe and Australia, rarely causes DILI. Clinical features suggest that FLX-induced liver injury is caused by immune- and inflammatory-related factors, but the mechanism of FLX-induced liver injury is unknown. The purpose of this study was to elucidate the mechanisms of FLX-induced liver injury in vivo. Plasma alanine aminotransferase, aspartate aminotransferase and total-bilirubin levels were significantly elevated in FLX-administered mice [1000 mg kg(-1) , intraperitoneally (i.p.)]. Toll-like receptor 4 (TLR4) ligands, such as high-mobility group box 1 (HMGB1) and S100A8/A9, were significantly increased in FLX-administered mice, and inflammatory factors, such as interleukin (IL)-1β, tumor necrosis factor-alpha (TNF-α), macrophage inflammatory protein (MIP)-2, CXC chemokine-ligand-1 (CXCL1) and monocyte chemoattractant protein (MCP)-1, were also significantly elevated. IL-17-related transcriptional factors and cytokines were increased, and the administration of recombinant IL-17 (2 mg per body weight, i.p.) resulted in an exacerbation of the FLX-induced liver injury. TLR4-associated-signal transduction may be involved in FLX-induced liver injury, and IL-17 is an exacerbating factor.
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