Colchicine protects mice from the lethal effect of an agonistic anti-Fas antibody

The aim of this study was to determine whether colchicine, which has been r eported to protect against various hepatotoxic insults, influences the susc eptibility of mice to the agonistic anti-Fas antibody, Jo2. All mice that w ere pretreated with colchicine (2 mg/kg) survived the lethal challenge of i ntraperitoneal administration of 10 mu g of Jo2, whereas all control mice p retreated with gamma-lumicolchicine succumbed to the challenge. Twelve micr ograms of Jo2 killed less than half of colchicine-pretreated mice and its l ethal effects were delayed relative to control mice, which all died within 8 hours. Other microtubule-disrupting agents such as Taxol, vinblastine, an d nocodazole also improved the survival of mice treated with the lethal dos e of Jo2. Histologic examination showed that colchicine protected against J o2-induced fulminant liver injury, and TUNEL assay demonstrated that colchi cine protected against massive apoptosis of hepatocytes. Hepatocytes isolat ed from colchicine-pretreated mice exhibited decreased susceptibility to Jo 2 induced apoptosis. In addition, colchicine pretreatment reduced surface e xpression of Fas and decreased Jo2- and TNF-alpha-induced apoptosis of cult ured hepatocytes in the presence of actinomycin D, but did not affect the s usceptibility of cultured sinusoidal endothelial cells to Jo2-induced apopt osis. Remarkably, Fas and TNF receptor-1 mRNA and intracellular protein lev els increased after colchicine treatment, indicating that colchicine protec ts against death ligand-induced apoptosis in the liver by decreasing death- receptor targeting to the cell surface.