Inflammatory disease and cancer with a decrease in Kupffer cell numbers in Nucling-knockout mice
Inflammatory disease and cancer with a decrease in Kupffer cell numbers in Nucling-knockout mice
复制标题
DOI：
10.1002/ijc.24789
复制
发表时间：
2010-03-01
影响因子：
6.4
通讯作者：
Fukui, Kiyoshi
中科院分区：
文献类型：
--
作者：
Sakai, Takashi;Liu, Li;Fukui, Kiyoshi
Nucling是一种与凋亡体相关的压力诱导蛋白。细胞色素c触发的凋亡体的形成是细胞凋亡中的一个关键启动事件。我们最近报道，Nucling还通过控制NF-kappa B的激活来调节细胞凋亡途径。在这里，我们发现在肝炎背景下自发发生的肝细胞癌在核基因敲除(KO)小鼠中比野生型(WT)小鼠更常见。生化血清检测显示Nucling-KO配偶存在潜在的肝功能障碍并伴有高胆固醇血症。在Nucling-KO小鼠的背景下，我们观察了肝脏中肿瘤坏死因子α的上调，自发的核因子-kappaB的激活和半乳糖凝集素-3的诱导表达。此外，我们还观察到KO小鼠的Kupffer细胞(KCs)数量减少。KCs对肝脏免疫系统很重要，起吞噬细胞或抗原提呈细胞(APC)的作用。我们发现Nucling-KO小鼠的KCs发生了凋亡，可能是通过上调肿瘤坏死因子α来实现的。这些观察结果表明，Nucling在肝脏中对核因子-kappaB信号的调节是重要的。我们认为Nucling缺陷可能是揭示导致肝炎和肝细胞癌发生的与核因子-kappaB相关的分子网络的有力工具。
Nucling is a stress-inducible protein associated with apoptosomes. The cytochrome c-triggered formation of apoptosomes represents a key-initiating event in apoptosis. We have recently reported that Nucling regulates the apoptotic pathway by controlling the activation of NF-kappa B as well. Here we show that hepatocellular carcinoma (HCC) arising spontaneously against a background of hepatitis occurred more frequently in Nucling-knockout (KO) mice than wild-type (WT) mice. Biochemical serum testing revealed potential liver dysfunction with hypercholesterolemia in Nucling-KO mates. In the background of Nucling-KO mice, we observed the up-regulation of TNF alpha, spontaneous NF-kappa B-activation and the induction of galectin-3 expression in liver. In addition, we observed a decrease in the number of Kupffer cells (KCs) in the KO mice. KCs are important for the hepatic immune system, acting as phagocytes or antigen-presenting cells (APCs). We found that KCs in Nucling-KO mice were apoptotic possibly through the up-regulation of TNF alpha. These observations indicate that Nucling is important for the regulation of NF-kappa B signals in liver. We propose that Nucling deficiency could be a powerful tool to reveal the NF-kappa B-related molecular networks leading to hepatitis and HCC development.