前列腺素E2信号通路和肿瘤坏死因子-α信号通路对骨髓来源树突状细胞功能的调节及白芍总苷的作用
Regulation of PGE2 signaling pathways and TNF-alpha signaling pathways on the function of bone marrow-derived dendritic cells and the effects of CP-25.
作者信息
Li Ying, Sheng Kangliang, Chen Jingyu, Wu Yujing, Zhang Feng, Chang Yan, Wu Huaxun, Fu Jingjing, Zhang Lingling, Wei Wei
机构信息
Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei 230032, Anhui Province, China.
Institute of Clinical Pharmacology, Anhui Medical University, Key Laboratory of Anti-inflammatory and Immune Medicine, Ministry of Education, Anhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine, Hefei 230032, Anhui Province, China.
出版信息
Eur J Pharmacol. 2015 Dec 15;769:8-21. doi: 10.1016/j.ejphar.2015.09.036. Epub 2015 Sep 28.
This study was to investigate PGE2 and TNF-alpha signaling pathway involving in the maturation and activation of bone marrow dendritic cells (DCs) and the effect of CP-25. Bone marrow DCs were isolated and stimulated by PGE2 and TNF-alpha respectively. The markers of maturation and activation expressed on DCs, such as CD40, CD80, CD83, CD86, MHC-II, and the ability of antigen uptake of DCs were analyzed by flow cytometry. The proliferation of T cells co-cultured with DCs, the signaling pathways of PGE2-EP4-cAMP and TNF-alpha-TRADD-TRAF2-NF-κB in DCs were analyzed. The results showed that both PGE2 and TNF-alpha up-regulated the expressions of CD40, CD80, CD83, CD86, and MHC-II, decreased the antigen uptake of DCs, and DCs stimulated by PGE2 or TNF-alpha could increase T cell proliferation. CP-25 (10(-5), 10(-6), and 10(-7)mol/l) decreased significantly the expressions of CD40, CD80, CD83, CD86 and MHC-II, increased the antigen uptake of DCs, and suppressed T cell proliferation induced by DCs. PGE2 increased the expressions of EP4, NF-κB and down-regulated cAMP level of DCs. TNF-alpha could also up-regulate TNFR1, TRADD, TRAF2, and NF-κB expression of DCs. CP-25 (10(-5), 10(-6), and 10(-7)mol/l) decreased the expressions of EP4 and NF-κB, increased cAMP level in DCs stimulated by PGE2. CP-25 (10(-5), 10(-6), and 10(-7)mol/l) also could down-regulate significantly TNFR1, TRADD, TRAF2, and NF-κB expression in DCs stimulated by TNF-alpha. These results demonstrate that PGE2 and TNF-alpha could enhance DCs functions by mediating PGE2-EP4-cAMP pathway, TNF-alpha-TNFR1-TRADD-TRAF2-NF-κB pathway respectively. CP-25 might inhibit the function of DCs through regulating PGE2-EP4-cAMP and TNF-alpha-TNFR1-TRADD-TRAF2-NF-κB pathways.
本研究旨在探讨参与骨髓树突状细胞（DCs）成熟和活化的前列腺素E2（PGE2）和肿瘤坏死因子-α（TNF-α）信号通路以及白芍总苷（CP-25）的作用。分别分离骨髓DCs并用PGE2和TNF-α刺激。通过流式细胞术分析DCs上表达的成熟和活化标志物，如CD40、CD80、CD83、CD86、主要组织相容性复合体II类（MHC-II）以及DCs的抗原摄取能力。分析与DCs共培养的T细胞增殖情况以及DCs中PGE2-EP4-环磷酸腺苷（cAMP）和TNF-α-肿瘤坏死因子受体相关死亡结构域蛋白（TRADD）-肿瘤坏死因子受体相关因子2（TRAF2）-核因子κB（NF-κB）信号通路。结果显示，PGE2和TNF-α均上调CD40、CD80、CD83、CD86和MHC-II的表达，降低DCs的抗原摄取，且PGE2或TNF-α刺激的DCs可增加T细胞增殖。CP-25（10⁻⁵、10⁻⁶和10⁻⁷mol/L）显著降低CD40、CD80、CD83、CD86和MHC-II的表达，增加DCs的抗原摄取，并抑制DCs诱导的T细胞增殖。PGE2增加DCs中EP4、NF-κB的表达并下调cAMP水平。TNF-α也可上调DCs中肿瘤坏死因子受体1（TNFR1）、TRADD、TRAF2和NF-κB的表达。CP-25（10⁻⁵、10⁻⁶和10⁻⁷mol/L）降低PGE2刺激的DCs中EP4和NF-κB的表达，增加cAMP水平。CP-25（10⁻⁵、10⁻⁶和10⁻⁷mol/L）还可显著下调TNF-α刺激的DCs中TNFR1、TRADD和TRAF2的表达以及NF-κB的表达。这些结果表明，PGE2和TNF-α可分别通过介导PGE2-EP4-cAMP通路、TNF-α-TNFR1-TRADD-TRAF2-NF-κB通路增强DCs功能。CP-25可能通过调节PGE2-EP4-cAMP和TNF-α-TNFR1-TRADD-TRAF2-NF-κB通路抑制DCs功能。
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