ToxSci Advance Access originally published online on July 25, 2003
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Toxicological Sciences 75, 300-308 (2003)
Copyright © 2003 by the Society of Toxicology
CARCINOGENICITY |
Cell Proliferation and Apoptosis Are Altered in Mice Deficient in the NF-
B p50 Subunit after Treatment with the Peroxisome Proliferator Ciprofibrate
,,,¶,1
* Graduate Center for Nutritional Sciences,
Graduate Center for Toxicology,
Department of Microbiology, Immunology, and Molecular Genetics,
Department of Nutrition and Food Science, and
¶ Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, Kentucky 40536
We previously showed that the peroxisome proliferator ciprofibrate increases hepatic NF-
B DNA binding activity in rats, mice, and hepatoma cell lines. Here, we analyzed the response to ciprofibrate in mice that lack the NF-B p50 gene (p50-/-). Wild-type and p50-/- mice were fed a diet with or without 0.01% ciprofibrate for 10 days. NF-B DNA binding activity was present and increased after ciprofibrate treatment in wild-type mice, but was not detected in p50-/- mice. The untreated p50-/- mice had a higher level of hepatic cell proliferation, as measured by BrdU labeling, than did untreated wild-type mice. However, the increase in proliferation was greater in ciprofibrate-fed wild-type mice than in ciprofibrate-fed p50-/- mice. The apoptotic index was low in wild-type mice in the presence or absence of ciprofibrate. Apoptosis was increased in untreated p50-/- mice compared to wild-type mice; apoptosis was reduced in p50-/- mice after ciprofibrate feeding. The c-Jun and JunB mRNA levels were higher in untreated p50-/- mice than in untreated control mice; c-Jun mRNA levels increased, whereas JunB mRNA levels decreased in both groups after ciprofibrate treatment. The c-Jun and JunB protein levels were the same in untreated wild-type and p50-/- mice and increased in both groups after ciprofibrate treatment. Several apoptosis-related mRNAs were higher in untreated p50-/- mice compared to untreated control mice; expression of these genes increased in both groups after ciprofibrate treatment. These data indicate that NF-B contributes to the proliferative and apoptotic changes that occur in the liver in response to ciprofibrate.
Key Words: liver; NF-B; proliferation; apoptosis; peroxisome proliferator; ciprofibrate; gene knock-out mice.
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