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.