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2015年第5期
高浓度胰岛素对树突状细胞LOX-1的表达的影响及其机制
The effect and mechanism of insulin enhances lectin-like oxidizied low-density lipoprotein receptor 1 expression in dendritic cell
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DOI:
作者:
陆浩 黄东 姚康 李晨光 常书福 戴宇翔 孙爱军 邹云增 钱菊英 葛均波
LU Hao, HUANG Dong, YAO Kang, LI Chenguang, CHANG Shufu, DAI Yuxiang, SUN Aijun, ZOU Yunzeng, QIAN Juying, GE Junbo
作者单位:
复旦大学附属中山医院心内科,上海市心血管病研究所,上海
Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai, China,
关键词:
胰岛素,树突状细胞,动脉粥样硬化,2型糖尿病,植物凝集素样氧化低密度脂蛋白受体-1
Keywords: insulin, dendritic cell, type 2 diabetes, atherosclerosis, LOX-1
摘要:
目的:高胰岛素血症是胰岛素抵抗的重要特征,并且是动脉粥样硬化发生的重要危险因素,植物凝集素样氧化低密度脂蛋白受体-1(LOX-1)参与了树突状细胞(DCs)摄取抗原和脂质提呈的过程,本研究观察高浓度胰岛素对DCs的LOX-1表达的影响并对其机制进行研究。 方法:采用免疫磁珠法分离人外周血CD14+单核细胞,经含100 ng/ml rhGM-CSF和50 ng/ml rhIL-4的RPMI-1640培养液培养5天,使其分化为未成熟DCs。分别加入终浓度为1 nmol/L、10 nmol/L、50 nmol/L、100 nmol/L浓度的胰岛素,另用PI3K抑制剂LY294002及MAPK抑制剂PD98059干预后再加入100 nmol/L浓度的胰岛素,干预24小时后,收集细胞。采用实时荧光定量PCR(Real-time PCR)和Western Blot方法检测LOX-1的表达情况。同时,用浓度为1 nmol/L和100 nmol/L的胰岛素干预DCs 24小时后,加入或不加入LOX-1阻断抗体,将DCs与Dil标记的ox-LDL共同孵育3小时,采用流式细胞术检测DCs吞噬ox-LDL情况。 结果:与浓度1 nmol/L胰岛素干预组相比,10 nmol/L、50 nmol/L、100 nmol/L浓度的胰岛素显著上调了LOX-1的mRNA和蛋白的表达(p<0.05),并且呈浓度依赖性;PD98059可明显抑制100 nmol/L胰岛素对DCs LOX-1表达的促进作用,但LY294002干预后LOX-1的表达未受明显抑制。另外,100 nmol/L胰岛素较1 nmol/L胰岛素明显促进DCs吞噬oxLDL的能力(p<0.05),该作用可部分被LOX-1抗体阻断。 结论:高浓度胰岛素明显上调DCs的LOX-1的表达,该作用主要是通过MAPK信号通路起作用,PI3K信号通路在其中并不起主要作用,而且高浓度胰岛素通过LOX-1促进DCs摄取oxLDL。本研究结果进一步证实了DCs在糖尿病动脉粥样硬化的发生发展中的重要作用。
Background: Insulin resistance is characterised by hyperinsulinaemia. Hyperinsulinaemia is considered as an independent participant in the atherogenic process. Therefore, we examined whether insulin regulates the expression of lectin-like oxidizied low-density lipoprotein receptor 1(LOX-1) responsible for oxidised low-density lipoprotein (oxLDL) uptake in dendritic cells (DCs), which is a critical step in atherogenesis. Methods: Peripheral blood mononuclear cells were purified using CD14+ immunomagnetic microbeads and incubated in RPMI-1640 medium supplemented with GM-CSF (100 ng/mL) and IL-4 (50 ng/mL) for 5 days. Immature DCs were cultured with different concentrations of insulin (1 nmol/L, 10 nmol/L, 50 nmol/L, and 100 nmol/L) in the absence or presence of LY294002 or PD98059 for 24 h. The expression of LOX-1 was determined by real-time PCR and Western blot analysis. Furthermore, DCs were incubated with DiI-labelled oxLDL. The DiI-oxLDL incorporated fraction was investigated by flow cytometry. Results: The incubation of DCs with insulin enhanced LOX-1 gene and protein expression in a dose-dependent manner. This effect was partially abolished by PD98059, which is a mitogen activated protein kinase (MAPK) inhibitor. However, LY294002 did not inhibit the effect of insulin on scavenger receptor expression. A high concentration of insulin increased the oxLDL-uptake capacity of DCs. Inhibition of LOX-1 significantly reduced oxLDL uptake. Conclusion: High concentration of insulin can increase the expression of LOX-1 in DCs, which can increase the oxLDL-uptake capacity of DCs. These results support the hypothesis that atherosclerosis is aggravated by hyperinsulinaemia-induced DCs oxLDL uptake and activation.
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