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ORIGINAL ARTICLE
Year : 2018  |  Volume : 131  |  Issue : 21  |  Page : 2575-2582

Overexpression of Dendritic Cell-Specific Intercellular Adhesion Molecule-3-Grabbing Nonintegrin in Dendritic Cells Protecting against Aspergillosis


1 Department of Pulmonary Medicine, Shanghai Institute of Respiratory Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
2 Laboratory of Molecular Iron Metabolism, The Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, Shijiazhuang, Hebei 050024, China

Correspondence Address:
Dr. Chang-Zhou Shao
Department of Pulmonary Medicine, Shanghai Institute of Respiratory Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0366-6999.244103

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Background: Dendritic cells (DCs) play an important role in host defense against pathogen infection. DC-specific intercellular adhesion molecule-3-grabbing nonintegrin (SIGN) is a group II C-type lectin receptor and specifically expressed on the surface of DCs. This study aimed to determine whether DC-SIGN affects intracellular signaling activation, Th1/Th2 imbalance and aspergillus immune evasion in aspergillus infection, and explore the application of DC-SIGN-modified DCs in immunotherapy. Methods: DCs were first obtained from the mononuclear cells of peripheral blood. The interferon (IFN)-γ and dexamethasone (Dex) were used to stimulate DCs. The expression of DC-SIGN, Th1 and Th2 cytokines, and the capacity of DCs in stimulating T cells proliferation and phagocytosis, and nuclear factor (NF)-κB activation were analyzed. In addition, adenovirus expression vector Ad-DC-SIGN was generated to transfect DCs. Mannan was used to block DC-SIGN signaling for confirming the involvement of DC-SIGN function in Aspergillus fumigatus (Af)-induced DCs maturation. The unpaired, two-tailed Student's t-test was used in the comparisons between two groups. Results: Exogenous IFN-γ could activate Af-induced DCs and promote the Th0 cells toward Th1 profile (interleukin [IL]-12 in IFN-γ/Af group: 50.96 ± 4.38 pg/ml; control/Af group: 29.70 ± 2.00 pg/ml, t = 10.815, P < 0.001). On the other hand, Dex inhibited the secretion of Th2 cytokines (IL-10 in Dex/Af group: 5.27 ± 0.85 pg/ml; control/Af group: 15.14 ± 1.40 pg/ml, t = 14.761, P < 0.001)), and successfully caused immunosuppression. After transfection with Ad-DC-SIGN, DCs have improved phagocytosis (phagocytosis rates in Ad-DC-SIGN group: 74.0% ± 3.4%; control group: 64.7% ± 6.8%, t = 3.104, P = 0.013). There was more Th1 cytokine secreted in the Af-induced DC-SIGN modified DCs (IL-12 in Ad-DC-SIGN/Af group: 471.98 ± 166.31 pg/ml; control/Af group: 33.35 ± 5.98 pg/ml, t = 6.456, P = 0.001), correlated to the enhanced NF-κB activation. Conclusion: Overexpressing DC-SIGN in DCs had a protective function on aspergillosis.

 

 Abstract in Chinese

树突状细胞表面DC-SIGN过表达对于曲霉感染起保护性作用

摘要

背景:树突状细胞(dendritic cells, DCs)在机体抗病原体感染中具有重要作用。DC-SIGN是主要表达于DCs表面的C型凝集素样受体中的一员。本研究旨在探讨DC-SIGN是否在曲霉感染中影响DCs细胞内信号传导、辅助T细胞Th1/Th2的平衡及曲霉菌免疫逃逸, 同时探索DC-SIGN基因修饰的树突状细胞用于免疫治疗的可能性。

方法:首先从外周血中提取了DCs。用IFN-γ和地塞米松分别刺激DCs后检测DC-SIGN的表达、Th1和Th2细胞因子分泌水平、DCs吞噬功能及刺激T细胞增殖能力、以及NF-κB的激活水平。此外,构建DC-SIGN腺病毒载体用于DCs转染。用甘露聚糖阻断DC-SIGN信号传导以明确DC-SIGN在烟曲霉刺激DCs成熟中的作用。未配对的双尾t检验用于组间比较。

结果:外源性IFN-γ刺激可以激活DCs并促使辅助T细胞向Th1细胞分化(IL-12水平在IFN-γ/Af 组为: 50.96±4.38pg/ml; 在control/Af组中为: 29.70±2.00 pg/ml, t = 10.815, P < 0.001)。此外,地塞米松抑制Th2细胞因子分泌(IL-10水平在Dex/Af组为:5.27±0.85pg/ml; 在control/Af 组为: 15.14±1.40pg/ml, t = 14.761, P < 0.001),并引起免疫抑制。在DC-SIGN基因转染的DCs中,Th1细胞因子的分泌(IL-12 水平在Ad-DC-SIGN/Af组为: 471.98±166.31 pg/ml; 在control/Af组为: 33.35±5.98 pg/ml, t = 6.456, P = 0.001)及NF-κB的激活均有上调,DCs的吞噬功能也有所增加(吞噬率在Ad-DC-SIGN 组为: 74.0±3.4%; control组为: 64.7±6.8%, t = 3.104, P = 0.013)。

结论树突状细胞表面DC-SIGN过表达对于曲霉感染起保护性作用。



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