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洛沙坦对人单核细胞源树突状细胞免疫功能的影响
Losartan inhibits immune maturation of human monocyte-derived dendritic cells induced by oxidized-low density lipoprotein and angiotensin II

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DOI:
作者:
黄东，陆浩，姚康，孙爱军，邹云增，葛均波
HUANG Dong, LU Hao, Yao Kang, SUN Aijun, Zou Yunzeng, 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
Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai
关键词:
树突状细胞；动脉粥样硬化；氧化低密度脂蛋白；血管紧张素II；洛沙坦
dendritic cells; atherosclerosis; oxidized low-density lipoprotein; angiotensin II; losartan
摘要:
目的 探讨洛沙坦对在免疫调控中起重要作用的树突状细胞（DCs）免疫功能的影响。 方法 采用密度梯度离心结合免疫磁珠法分离人外周血CD14+单核细胞，经含100ng/ml rhGM-CSF和50ng/ml rhIL-4的RPMI-1640培养液培养诱导分化为未成熟DCs。经不同浓度的OxLDL和Ang II干预24小时，另用10μM的洛沙坦预干预后再加入OxLDL或Ang II干预24小时，以PBS作为阴性对照，采用流式细胞术检测细胞免疫表型（CD83、HLA-DR），ELISA法检测细胞培养上清液中细胞因子（IL-12和IFN-γ）的浓度和OxLDL组上清液中Ang II的浓度。 结果 OxLDL和Ang II干预呈浓度依赖性上调DCs表面成熟度标志CD83和HLA-DR的表达，且分泌细胞因子IL-12和IFN-γ水平明显升高，10μM洛沙坦预处理可明显抑制OxLDL和Ang II诱导的DCs成熟。不同浓度OxLDL干预可浓度依赖性促进DCs自分泌Ang II，10μM的洛沙坦预处理对Ang II的分泌无明显影响。 结论 OxLDL可通过促进DCs自分泌Ang II而与之形成活化DCs的协同作用，洛沙坦可抑制OxLDL和Ang II诱导的DCs免疫成熟，这可能是ARB类药物抗AS的新机制。
Objective To investigate the effects of angiotensin II receptor 1 antagonist (ARB) losartan on the immune maturation of human monocyte-derived dendritic cells (DCs)．Methods Human peripheral blood mononuclear cells (PBMCs) were separated by density gradient centrifugation and the monocytes were purified from PBMCs by positive selection with anti-CD14 magnetic beads. After cultured in RPMI-1640 medium containing recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF, 100ng/ml) and recombinant human interleukin-4 (rhIL-4, 50ng/ml) for 5 days，monocytes were derived into immature DCs．On culture day 6, cells were treated with various concentrations of oxidized low-density lipoprotein (OxLDL, 10、20、50μg/ml) or angiotensin II (Ang II, 1、10、100nM) for 24 hours. The other groups of human monocyte-derived DCs were pretreated with losartan (10μM) for 24 hours and subsequently stimulated with 50μg/ml OxLDL or 100nM Ang II for 24 hours．The immunophenotypic expressions (HLA-DR and CD83) were analyzed by FACS. The cytokine secretions of culture supernatants (IL-12 and IFN-γ) and the Ang II secretion in the OxLDL-treated groups were measured with ELISA．Results OxLDL and Ang II could induce the maturation of human monocyte-derived DCs, stimulate CD83, HLA-DR expressions and IL-12, IFN-γ secretions in a dose-dependent manner, which were suppressed by losartan pretreatment. OxLDL could promote the autocrine secretion of Ang II by DCs in a dose-dependent manner, which was not affected by losartan pretreatment. Conclusion The anti-atherosclerosis effect of ARB losartan was partly mediated by attenuating the OxLDL- and Ang II-induced immune maturation of human monocyte-derived DCs.

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