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Role of Plant Sterol and Sterolin in Macrophages and T Lynphocytes

植物甾醇和甾醇在巨噬细胞和 T 淋巴细胞中的作用

基本信息

批准号：
18590977
负责人：
TSUKAMOTO Kazuhisa
金额：
$ 2.53万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590977/
关键词：
macrophage plant sterol inflammation cytokine sterolin atherosclerosis

项目摘要

It has been known that the gene mutations in ABCG5 or ABCG8 result in phytosterolemia which is characterized with the premature atherosclerosis. However, the precise mechanism underlying in the atherogenesis in phytosterolemia has not been elucidated. In this study, we evaluated gene expressions of ABCG5 and ABCG8 in macrophages, and sterol-induced cytokine production in macrophages. Human macrophages, mouse peritoneal macrophages, J774. Al cells and RAW264.7 cells were utilized in this study. Neither ABCG5 nor ABCG8 were expressed in macrophages; even the cholesterol loading or stimulation with LXR agonist to the cells did not result in the expressions. The cells were loaded with cholesterol, sitosterol or campesterol in low (16 uM) and high (160 uM) concentrations, and cytokines production from the cells were examined. When the sterols were loaded to RAW264.7 cells in low concentration, sitosterol induced slight increase in cytokines in case they were stimulated with LPS. In high sterol loading with LPS stimulation, cholesterol induced prominent increase in cytokine production in both J774. Al cells and RAW264.7 cells, while sitosterol and campesterol reduced the production of cytokines. Due to the accidents of the animal facility of the Tokyo University, we could not perform sufficient animal experiments; however, the preliminary study revealed that the plasma total cholesterol levels and cytokine levels in the double knock out mice in apoE and sterolins might be lower than those of apoE deficient mice. These results indicate that the macrophages would not the main player in the atherogenesis of phytosterolemia. Through this study, we found that the splicing of ABCG5 cDNA in the liver is different from that in the intestine, which suggests that the sterolin 1 in the liver would behave differently from that in the intestine.

已知ABCG 5或ABCG 8基因突变导致以过早动脉粥样硬化为特征的植物甾醇血症。然而，植物甾醇血症动脉粥样硬化形成的确切机制尚未阐明。在这项研究中，我们评估了ABCG 5和ABCG 8在巨噬细胞中的基因表达，以及巨噬细胞中甾醇诱导的细胞因子产生。人巨噬细胞，小鼠腹腔巨噬细胞，J774。本研究使用A1细胞和RAW264.7细胞。ABCG 5和ABCG 8在巨噬细胞中均不表达;即使胆固醇负荷或用LXR激动剂刺激细胞也不导致表达。用低浓度（16 μ M）和高浓度（160 μ M）的胆固醇、谷甾醇或菜油甾醇加载细胞，并检查细胞的细胞因子产生。当低浓度的甾醇负载到RAW264.7细胞时，谷甾醇诱导细胞因子在LPS刺激的情况下轻微增加。在高固醇负荷与LPS刺激，胆固醇诱导细胞因子的生产在两个J774显着增加。A1细胞和RAW264.7细胞，而谷甾醇和菜油甾醇减少细胞因子的产生。由于东京大学动物设施的事故，我们无法进行充分的动物实验;然而，初步研究显示，apoE和固醇双敲除小鼠的血浆总胆固醇水平和细胞因子水平可能低于apoE缺陷小鼠。这些结果表明，巨噬细胞不是植物甾醇血症动脉粥样硬化形成的主要参与者。通过本研究，我们发现ABCG 5 cDNA在肝脏中的剪接方式与在肠道中的剪接方式不同，这表明Sterolin 1在肝脏中的行为与在肠道中的行为不同。