Protective effect of SKLB010 against d-galactosamine/lipopolysaccharide-induced acute liver failure via nuclear factor-κB signaling pathway in macrophages

Abstract

Acute liver failure is characterized by the sudden loss of hepatic function and a high mortality. SKLB010, a derivative of thiazolidinediones, has been proved to be effective in protecting mice from acute liver failure caused by concanavalin A and carbon tetrachloride in our previous work. The purpose of the current study was to evaluate whether SKLB010 could prevent acute liver injury caused by d-galactosamine/lipopolysaccharide (LPS) in mice, and to investigate the underlying mechanisms. In the macrophage-mediated D-GalN/LPS model of acute liver injury, serum enzyme activity was suppressed and liver injury was attenuated by SKLB010. The serum levels of TNF-α and hepatic TNF-α mRNA expression were also markedly decreased after the treatment of SKLB010. In the liver of mice receiving injections of D-GalN/LPS, hepatocytes apoptosis and the infiltration of monocytes/macrophages were blocked by SKLB010. Furthermore, the survival rate of mice following D-GalN/LPS treatment was significantly improved by a single injection with SKLB010. In vivo, the luminescence intensity was suppressed by SKLB010 in NF-κB-luc mice after D-GalN/LPS treatment. In vitro, the production of tumor necrosis factor (TNF)-α and nitrite/nitrate in LPS-stimulated RAW264.7 macrophages was decreased by SKLB010 in a dose-dependent manner. Our further studies demonstrated that SKLB010 inhibited the phosphorylation of IκBα and p38MAPK, and the DNA binding activity of NF-κB in RAW264.7 cells. In conclusion, treatment with only a single injection of SKLB010 could significantly attenuate acute inflammation in mice induced by D-GalN/LPS, and these effects are likely associated with the inhibition of NF-κB activity.