Abstract
Drug-induced liver injury has become a serious public health problem. Although the mechanism of acetaminophen (APAP)-induced liver injury has been studied for decades it has not been fully elucidated. In-depth study into the mechanisms underlying APAP-induced liver injury may provide useful information for more effective prevention and treatment. In the present study, the role of C-X-C motif chemokine ligand-9 (CXCL9) in APAP-induced liver injury was investigated thus providing a novel direction for the prevention and treatment of drug hepatitis. A total of 20 fasting male patients ingested APAP tablets at Nanjing First Hospital. In addition, wild type (WT) mice were treated with 250 mg/kg APAP or isodose PBS for 1, 3, 6 and 12 h, respectively. Results from reverse-transcription-quantitative polymerase chain reaction analyses demonstrated that CXCL9 mRNA levels were increased in the blood of patients who took APAP in a fasting state and in the livers of APAP-treated WT mice, compared with their respective controls. Hepatocyte apoptosis in the liver tissue of APAP-treated mice decreased following administration of a CXCL9 neutralizing antibody. Caspase-3, caspase-8 and phosphorylated-AKT (S437) were activated in primary hepatocytes isolated from WT mice following CXCL9 treatment. However, no significant differences in expression of caspase-3, caspase-8 and p-AKT (S437) were detected in hepatocytes isolated from C-X-C motif chemokine receptor 3 (CXCR3)-/- mice following CXCL9 treatment. After CXCL9 administration, WT mice exhibited higher serum levels of aspartate transaminase and increased caspase-3 and caspase-8 activity in liver tissue compared with controls. The same trends were not observed in CXCR3-/- mice. In conclusion, CXCL9 regulated APAP-induced liver injury through stimulation of hepatocyte apoptosis via binding to CXCR3. These findings provide a novel prevention and treatment strategy for DILI.