Cell proliferation and apoptosis are altered in mice deficient in the NF-kappaB p50 subunit after treatment with the peroxisome proliferator ciprofibrate.
We previously showed that the peroxisome proliferator ciprofibrate increases hepatic NF-kappaB DNA binding activity in rats, mice, and hepatoma cell lines. Here, we analyzed the response to ciprofibrate in mice that lack the NF-kappaB p50 gene (p50-/-). Wild-type and p50-/- mice were fed a diet with or without 0.01% ciprofibrate for 10 days. NF-kappaB 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-kappaB contributes to the proliferative and apoptotic changes that occur in the liver in response to ciprofibrate.
Tharappel
Job C
JC
Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, Kentucky 40536, USA.
Nalca
Aysegul
A
Owens
Aaron B
AB
Ghabrial
Leila
L
Konz
Elizabeth C
EC
Glauert
Howard P
HP
Spear
Brett T
BT
D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D002995:Clofibric Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity*; D004032:Diet; D058607:Fibric Acids; D020287:In Situ Nick-End Labeling; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D016328:NF-kappa B / Q000172:deficiency* / Q000235:genetics; D052002:NF-kappa B p50 Subunit; D020025:Peroxisome Proliferators / Q000008:administration & dosage / Q000633:toxicity*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism
D058607:Fibric Acids; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D020025:Peroxisome Proliferators; D016755:Proto-Oncogene Proteins c-jun; D012333:RNA, Messenger; D002995:Clofibric Acid; C019304:ciprofibrate