Involvement of immune- and inflammatory-related factors in flucloxacillin-induced liver injury in mice

ABSTRACT 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. Copyright © 2014 John Wiley & Sons, Ltd. Flucloxacillin (FLX), which is a β‐lactam antibiotic of the penicillin class, rarely causes drug‐induced liver injury. The purpose of this study was to elucidate the mechanisms of FLX‐induced liver injury in vivo. Toll‐like receptor 4 (TLR4) ligands and inflammatory factors were significantly increased in FLX‐administered mice. IL‐17‐related transcriptional factors and cytokines were increased, and the administration of recombinant IL‐17 resulted in an exacerbation of the FLX‐induced liver injury.TLR4‐associated‐signal transduction and IL‐17 may be involved in FLX‐induced liver injury.