氧化低密度脂蛋白（ox-LDL）诱导的组织蛋白酶S（Cat S）高表达在树突状细胞（DCs）DCs激活中的作用研究

Increasing evidences have demonstrated that atherosclerosis is an inflammatory disease.Dendritic cells (DCs) are highly specialized antigen-presenting cells (APCs) that play a central role in the initiation and regulation of both innate and adaptive immune responses. DCs play an important role in atherosclerosis because of their high antigen uptake capacity, processing, and their special ability to activate T cells. The relevance of dendritic cells (DCs) and oxidized low-density lipoproteins (ox-LDL) to the pathogenesis of atherosclerosis is well characterized. In our previous studies, iTRAQ was used to investigate the protein profile of immature and ox-LDL-treated DCs. The most interesting finding was that ox-LDL enhanced the expression of intracellular cathepsin S （Cat S）, significantly. Accumulating evidences indicate that，throughout the development and progression of atherosclerosis, Cat S are involved in crucial pathological processes including the antigen presentation, apoptosis, lipid metabolism, inflammation, matrix remodeling, neovascularization, restenosis, neointima formation and plaque rupture. In this study we will focus on: ① Analysis the relevance of up-regulated Cat S and the immunological function changes of DCs. ② Analysis the role of mitogen-activated protein kinase (MAPK) and NF-κB in the process of up-regulated Cat S. Our present data may provide a better understanding of the role of up-regulated Cat S in the course of immunological function changes of DCs and may provide a beneficial clue for comprehensively understanding the functions of DCs in the pathogenesis of atherosclerosis.

免疫炎症反应贯穿于动脉粥样硬化(AS)发病的各个环节。树突状细胞(DCs)是体内功能最强大的专职抗原递呈细胞，它能有效地摄取和递呈抗原，在免疫反应的诱导和调节中发挥关键作用。DCs和氧化低密度脂蛋白(ox-LDL)与AS的发病密切相关。前期研究中我们应用同位素标记蛋白质相对和绝对定量分析(iTRAQ)技术发现ox-LDL可使DCs内组织蛋白酶S(CatS)高表达。大量研究表明，CatS参与抗原递呈、脂质代谢、炎症反应、细胞外基质降解、斑块破裂和血管内膜形成等多个AS发病过程。本课题拟：①检测ox-LDL诱导的CatS高表达对DCs免疫功能的影响；②探讨丝裂原激活的蛋白激酶(MAPK)和核因子-κB(NF-κB)信号通路是否参与ox-LDL诱导的CatS高表达。本项目的完成将进一步明确ox-LDL诱导的CatS高表达在DCs活化中的作用，为深人理解DCs与AS发病的关系提供一个新视角。

免疫炎症反应贯穿于动脉粥样硬化(Atherosclerosis，AS)发病的各个环节。树突状细胞(Dendritic Cells DCs)是体内功能最强大的专职抗原递呈细胞，它在免疫反应的诱导和调节中发挥关键作用。DCs与AS的发病密切相关。大量研究表明，Cat S参与抗原递呈、脂质代谢、炎症反应和斑块破裂等多个AS发病过程。本课拟研究:（1）、Cat S对人外周血单核细胞来源的DCs免疫功能的影响。（2）、探讨Cat S诱导的DCs免疫功能变化过程中可能的分子机制，尤其关注丝裂原激活的蛋白激酶(Mitogen-activated protein kinase，MAPK)信号通路和核因子-κB (NF-κB) 信号通路。本课题组研究结果研究结果显示：1、Cat S能够促进DCs成熟和免疫活化。主要表现在：（1）、Cat S能刺激人单核细胞来源的DCs表面共刺激分子CD80、CD86、CD40和MHC-Ⅱ类分子HLA-DR的高表达。（2）、Cat S能促进DCs分泌炎症因子IL-12和TNF-α。（3）、Cat S能增强DCs刺激的T淋巴细胞增殖反应。2、CatS对DCs免疫功能的影响其内在的分子机制至少部分是通过P38-MAPK信号转导通路实现的。主要表现在：（1）、特异性P38-MAPK通道阻断剂能部分抑制Cat S诱导的DCs表面分子CD86、CD80、CD40和HLA-DR高表达；能部分减少IL-12和TNF-α的分泌；还能够部分阻断Cat S诱导的DCs对T淋巴细胞的激活。（2）、特异性ERK-MAPK通道阻断剂和JNK-MAPK通道阻断剂预处理对Cat S诱导的DCs免疫功能变化无明显抑制作用。总之，以上实验结果说明：Cat S能够促进DCs成熟并能增强DCs免疫活化，其内在的分子机制至少部分是通过P38-MAPK信号转导通路实现的。通过本实验初步明确了CatS对DCs免疫功能的影响及其部分分子机制，这可能为进一步研究DCs和Cat S参与AS的病理机制提供新的思路。随着对DCs与Cat S研究的不断深入，将会为更好的理解AS发病机制提供新视角。

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