Notch Ligand Delta-Like 4-Pretreated Dendritic Cells Alleviate Allergic Airway Responses by Enhancing IL-10 Production
Notch Ligand Delta-Like 4-Pretreated Dendritic Cells Alleviate Allergic Airway Responses by Enhancing IL-10 Production
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DOI：
10.1371/journal.pone.0063613
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发表时间：
2013-05-16
期刊：
影响因子：
3.7
通讯作者：
Lee, Yueh-Lun
中科院分区：
文献类型：
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作者：
Huang, Huei-Mei;Hsiao, George;Lee, Yueh-Lun
Notch通路参与细胞增殖、分化和凋亡过程，影响各器官的发育和功能。树突状细胞（Dendritic cells, dc）作为专业的抗原呈递细胞（antigen-presenting cells, APCs），通过抗原刺激诱导T细胞活化并促进T细胞分化。研究表明APCs中的Notch配体delta-like 4 （Dll4）与th1型反应的刺激有关。然而，Dll4在dc的激活和功能中的调节作用尚不清楚。在这项研究中，我们证明了通过卵清蛋白（OVA）刺激激活dll4预处理的骨髓源性dc，可以表达高水平的白细胞介素(IL)-10，而不会减少IL-12的产生。相比之下，通过脂多糖（LPS）或OVA刺激，促炎细胞因子IL-1 β、IL-6和肿瘤坏死因子(TNF)- α在dll4预处理的DCs中下降。与完全成熟的dc相比，这些半成熟样dc中MHC II类CD40表达水平较低，CD80和CD86分子表达水平较高。Dll4 Notch信号也增强了dc中Dll1、Dll4和Jagged1 Notch配体mRNA的表达。dll4修饰的dc刺激ova特异性CD4(+) T细胞增殖的能力降低，但在这些活化的T细胞中积极促进大量IL-10的产生。此外，在建立的哮喘动物模型中检测了dll4修饰的dc的免疫调节作用。在OVA免疫小鼠中，经OVA脉冲和dll4预处理的dc过过性转移后，OVA攻击诱导OVA特异性免疫球蛋白E （IgE）和IgG（2a）抗体的产生降低，支气管肺泡灌洗液中eotaxin、角化细胞衍生趋化因子（KC）、IL-5和IL-13的释放降低，气道高反应性减弱，并促进脾脏中IL-10和干扰素(IFN)- γ的产生增加。总之，我们的研究结果阐明了Dll4在dc表型和功能中的新作用，并为操纵T细胞驱动的有害免疫疾病提供了一种新的方法。
The Notch pathway plays a role in the processes of cell proliferation, differentiation, and apoptosis, which affect the development and function of various organs. Dendritic cells (DCs), as professional antigen-presenting cells (APCs), induce T cell activation and promote T cell differentiation by antigen stimulation. Research has shown that Notch ligand delta-like 4 (Dll4) in APCs is associated with stimulation of a Th1-type response. However, the regulatory roles of Dll4 in the activation and function of DCs have yet to be clearly elucidated. In this study, we demonstrated that activation of Dll4-pretreated bone marrow-derived DCs by performing ovalbumin (OVA) stimulation expressed a high level of interleukin (IL)-10 without diminishing IL-12 production. By contrast, the proinflammatory cytokines, IL-1 beta, IL-6, and tumor necrosis factor (TNF)-alpha, decreased in Dll4-pretreated DCs by performing either lipopolysaccharide (LPS) or OVA stimulation. Compared to fully mature DCs, lower levels of MHC class II CD40 and higher levels of CD80 and CD86 molecules were expressed in these semi-mature like DCs. Dll4 Notch signaling also enhanced Notch ligand mRNA expression of Dll1, Dll4, and Jagged1 in DCs. Dll4-modified DCs exhibited a reduced capacity to stimulate the proliferation of OVA-specific CD4(+) T cells, but actively promoted large amounts of IL-10 production in these activated T cells. Furthermore, immunomodulatory effects of Dll4-modified DCs were examined in an established asthmatic animal model. After adoptive transfer of OVA-pulsed plus Dll4-pretreated DCs in OVA-immunized mice, OVA challenge induced lower OVA-specific immunoglobulin E (IgE) and higher IgG(2a) antibody production, lower eotaxin, keratinocyte-derived chemokine (KC), IL-5, and IL-13 release in bronchial alveolar lavage fluid, attenuated airway hyper-responsiveness, and promoted higher IL-10 and interferon (IFN)-gamma production in the spleen. In summary, our findings elucidate the new role of Dll4 in the phenotype and function of DCs and provide a novel approach for manipulating T cell-driven deleterious immune diseases.