IL-32γ Inhibits Acetaminophen-Induced Acute Hepatotoxicity through Inactivation of NF-κB and Stat1 Signals

Although several studies have shown physiological functions of interleukin (IL)-32, the role of IL-32 in liver has not yet been reported. This study was initiated to examine the effects of IL-32 gamma on APAP-induced acute hepatic failure in IL-32 gamma transgenic mice. IL-32 gamma overexpressing and non-transgenic mice received 500 mg/kg Acetoaminophen (APAP) intraperitoneally. Serum alanine transaminase and aspartate transaminase were significantly lower in the APAP treated IL-32 gamma overexpressing mice compared with those APAP-treated non-transgenic. IL-32 gamma markedly reduced a restricted area of the necrosis and inflammation. APAP-induced reduced glutathione depletion, induction of nitric oxide and lipid peroxidation, and cytochrome P4502E1 expression was significantly lowered in the IL-32 gamma overexpressing mice. Elevation of Kupffer cells and natural killer cells by APAP were reduced in the IL-32 gamma overexpressing mice. The expression of IL-1 alpha, IL-1ra, macrophage inflammatory protein-2, C-C motif chemokine ligand 5 and tissue inhibitor of metalloproteinase-1 was increased by APAP in non-transgenic mice, and were lowered in the IL-32 gamma overexpressing mice. Moreover, APAP-induced nuclear transcription factor-kappa B (NF-kappa B) and signal transducers and activators of transcription 1 (STAT1) activities were greatly lowered in the IL-32 gamma overexpressing mice. The results indicate that IL-32 gamma could effectively inhibit drug-induced hepatic failure, and reduce the number of cytotoxic immune cells and pro-inflammatory cytokine production through reduced activities of NF-kappa B and STAT1. This might be attributable to lowering APAP-induced liver toxicity in IL-32 gamma overexpressing mice.