Colchicine protects mice from the lethal effect of an agonistic anti-Fas antibody
Guoping Feng, Neil Kaplowitz
Guoping Feng, Neil Kaplowitz
Published February 1, 2000
Citation Information: J Clin Invest. 2000;105(3):329-339. https://doi.org/10.1172/JCI7398.
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Colchicine protects mice from the lethal effect of an agonistic anti-Fas antibody

Abstract

The aim of this study was to determine whether colchicine, which has been reported to protect against various hepatotoxic insults, influences the susceptibility of mice to the agonistic anti-Fas antibody, Jo2. All mice that were pretreated with colchicine (2 mg/kg) survived the lethal challenge of intraperitoneal administration of 10 μg of Jo2, whereas all control mice pretreated with γ-lumicolchicine succumbed to the challenge. Twelve micrograms of Jo2 killed less than half of colchicine-pretreated mice and its lethal effects were delayed relative to control mice, which all died within 8 hours. Other microtubule-disrupting agents such as Taxol, vinblastine, and nocodazole also improved the survival of mice treated with the lethal dose of Jo2. Histologic examination showed that colchicine protected against Jo2-induced fulminant liver injury, and TUNEL assay demonstrated that colchicine protected against massive apoptosis of hepatocytes. Hepatocytes isolated from colchicine-pretreated mice exhibited decreased susceptibility to Jo2-induced apoptosis. In addition, colchicine pretreatment reduced surface expression of Fas and decreased Jo2- and TNF-α–induced apoptosis of cultured hepatocytes in the presence of actinomycin D, but did not affect the susceptibility of cultured sinusoidal endothelial cells to Jo2-induced apoptosis. Remarkably, Fas and TNF receptor-1 mRNA and intracellular protein levels increased after colchicine treatment, indicating that colchicine protects against death ligand–induced apoptosis in the liver by decreasing death-receptor targeting to the cell surface.

Authors

Guoping Feng, Neil Kaplowitz

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(a) Effect of colchicine on apoptosis induced by Jo2 or TNF-α in actinom...
(a) Effect of colchicine on apoptosis induced by Jo2 or TNF-α in actinomycin D–sensitized hepatocytes. Hepatocytes were pretreated with 1 μM colchicine or γ-lumicolchicine for 12 hours and were then exposed to 100 ng/mL Jo2 antibody or 5,000 U/mL TNF-α in the presence of 0.5 μg/mL actinomycin D (ActD) for 8 hours. The treatments are indicated below each bar. Apoptosis was assessed as described in Figure 4a. Results are mean ± SD for 3 independent experiments. *P < 0.05 and **P < 0.01 vs. γ-lumicolchicine control by unpaired Student’s t test. (b) Effect of nocodazole on apoptosis induced by Jo2 or TNF-α in actinomycin D–sensitized hepatocytes. Hepatocytes were pretreated with 20 μM nocodazole for 12 hours and then exposed to 100 ng/mL Jo2 antibody or 5,000 U/mL TNF-α in the presence of 0.5 μg/mL actinomycin D for 8 hours. Treatments are indicated below each bar. Apoptosis was assessed as described in Figure 4a. Results are mean ± SD for 3 independent experiments. *P < 0.05 and **P < 0.01 vs. γ-lumicolchicine control by unpaired Student’s t test. Noc, nocodazole.