Secoisolariciresinol and isotaxiresinol inhibit tumor necrosis factor-α-dependent hepatic apoptosis in mice

Abstract

The effects of secoisolariciresinol ( 1) and isotaxiresinol ( 2), two major lignans isolated from the wood of Taxus yunnanensis, on tumor necrosis factor-α (TNF-α)-dependent hepatic apoptosis induced by D-galactosamine ( d-GalN)/lipopolysaccharide (LPS) were investigated in mice. Co-administration of d-GalN (700 mg/kg) and LPS (10 μg/kg) resulted in a typical hepatic apoptosis characterized by DNA fragmentation and the formation of apoptotic bodies. Serum glutamic pyruvic transaminase (sGPT) and glutamic oxaloacetic transaminase (sGOT) levels were also raised at 8 h after d-GalN/LPS intoxication due to a severe necrosis of hepatocytes. Pre-administration of 1 or 2 (50, 10 mg/kg, i.p.) 12 and 1 h before d-GalN/LPS significantly reduced DNA fragmentation and prevented chromatin condensation, apoptotic body formation and hepatitis. Pro-inflammatory cytokines such as TNF-α and interferon-γ (IFN-γ) secreted from LPS-activated macrophages are important mediators of hepatocyte apoptosis in this model. Pre-treatment with 1 or 2 significantly inhibited the elevation of serum TNF-α and IFN-γ levels. In a separate experiment, both lignans had a significant dose-dependent protective effect on d-GalN/TNF-α-induced cell death in primary cultured mouse hepatocytes and TNF-α-mediated cell death in murine L929 fibrosarcoma cells. These results indicated that 1 and 2 prevent d-GalN/LPS-induced hepatic injury by inhibiting hepatocyte apoptosis through the blocking of TNF-α and IFN-γ production by activated macrophages and direct inhibition of the apoptosis induced by TNF-α.