Cell proliferation and apoptosis are altered in mice deficient in the NF-κB p50 subunit after treatment with the peroxisome proliferator ciprofibrate
Cell proliferation and apoptosis are altered in mice deficient in the NF-κB p50 subunit after treatment with the peroxisome proliferator ciprofibrate
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DOI：
10.1093/toxsci/kfg201
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发表时间：
2003-10-01
影响因子：
3.8
通讯作者：
Spear, BT
中科院分区：
文献类型：
--
作者：
Tharappel, JC;Nalca, A;Spear, BT
我们之前的研究表明，过氧化物酶体增殖剂环丙贝特增加了大鼠、小鼠和肝癌细胞系中肝脏NF-kappaB DNA结合活性。在这里，我们分析了缺乏NF-kappaB p50基因（p50(-/-)）的小鼠对环丙贝特的反应。野生型和p50（-/-）型小鼠分别饲喂含或不含0.01%环丙贝特的日粮10天。在野生型小鼠中，经环丙贝特处理后，NF-kappaB DNA结合活性存在并增加，但在p50（-/-）小鼠中未检测到。通过BrdU标记测量，未经处理的p50（-/-）小鼠比未经处理的野生型小鼠具有更高水平的肝细胞增殖。然而，在环丙贝特喂养的野生型小鼠中，增殖的增加比环丙贝特喂养的p50（-/-）小鼠更大。凋亡指数。在存在或不存在环丙贝特的野生型小鼠中均较低。与野生型小鼠相比，未处理的p50（-/-）小鼠细胞凋亡增加；给药后p50（-/-）小鼠细胞凋亡减少。p50（-/-）未处理小鼠的c-Jun和JunB mRNA水平高于未处理对照组小鼠；两组c-Jun mRNA水平均升高，JunB mRNA水平均降低。c-Jun和JunB；在未经治疗的野生型和p50（-/-）小鼠中，蛋白质水平相同，在服用环丙贝特后，两组的蛋白质水平均升高。与未处理的对照组小鼠相比，未处理的p50（-/-）小鼠中几种凋亡相关mrna更高；这些基因的表达在两组服用环丙贝特后均增加。这些数据表明，NF-kappaB有助于肝细胞对环丙贝特的增殖和凋亡变化。
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 wildtype 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.