黄芪四君子汤调节T细胞PD1泛素化水平重塑肿瘤免疫微环境抑制胃癌增殖的研究

Huangqi Sijunzi Decoction Restrained Gastric Cancer Proliferation via Regulating the Level of PD1 Ubiquitination on T Cells and Remodeling the Tumor Immune Microenvironment

    摘要
  • 摘要:
      目的  探讨黄芪四君子汤对MFC胃癌荷瘤小鼠肿瘤增殖及免疫功能的影响。
      方法  建立C57BL/6小鼠MFC胃癌皮下荷瘤模型, 采用随机数字表法, 将24只C57BL/6小鼠分为空白对照组、模型组、中药低剂量组(6.24 g·kg-1)、中药高剂量组(12.48 g·kg-1), 每组6只; 记录小鼠体质量, 计算肿瘤体积; ELISA法检测各组小鼠外周血中IFN-γ、IL-2、IL-8和TNF-α表达水平; 应用流式细胞术分别检测小鼠肿瘤、脾脏和胸腺中CD4+、CD8+、PD1+ T细胞亚群的表达水平; 检测小鼠肿瘤中PD1泛素化水平。
      结果  与空白对照组比较, 皮下荷瘤模型组小鼠体质量增加(P < 0.05)，外周血中IFN-γ、IL-2和TNF-α表达水平降低(P < 0.001)、IL-8表达升高(P < 0.05)。与模型组相比, 中药高剂量组小鼠肿瘤大小明显低于模型组(P < 0.05)，外周血中IFN-γ、IL-2和TNF-α表达水平显著上升(P < 0.001，P < 0.01), 而IL-8的表达水平显著降低(P < 0.05);中药高剂量组小鼠的肿瘤、脾脏和胸腺中CD4+、CD8+T细胞亚群表达均增加(P < 0.001), PD1+T细胞则随着其泛素化水平增加(P < 0.01)而表达下降(P < 0.001)。
      结论  黄芪四君子汤可上调MFC荷瘤小鼠CD4+、CD8+T细胞表达, 调节外周血中细胞因子的表达水平, 并通过增加T细胞胞内泛素化水平, 促使PD1表达下调, 从而抑制胃癌细胞的增殖。

     

    Abstract:
      OBJECTIVE  To evaluate the effects of Huangqi Sijunzi Decoction on tumor proliferation and immune function of MFC gastric cancer bearing mice.
      METHODS  The MFC gastric cancer subcutaneous tumor model of C57BL/6 mouse was established. 24 C57BL/6 mice were divided into control group, model group, low dose Chinese medicine group (6.24 g· kg-1) and high dose Chinese medicine group (12.48 g· kg-1), with 6 mice in each group. The body weight and tumor volume of these mice were recorded. Expression levels of IFN-γ, TNF-α, IL-2 and IL-8 in peripheral blood of mice in each group were detected by ELISA. The expression levels of CD4+, CD8+, and PD1+ T cell subsets in the tumor, spleen, and thymus of mice were analyzed by flow cytometry. Detect PD1 ubiquitination levels in mouse tumors.
      RESULTS  Compared with control group, the body weight was increased (P < 0.05), the expression of IFN-γ, TNF-α, IL-2 were decreased (P < 0.001), and the expression of IL-8 was increased in model group (P < 0.05). Compared with model group, the tumor volume of mice in high dose Chinese medicine group was remarkable declined (P < 0.05). The expression levels of IFN-γ, IL-2, TNF-α in mouse peripheral blood increased (P < 0.01, P < 0.001), but the expression level of IL-8 decreased (P < 0.05). The expression of CD4+ and CD8+ T cell subsets in tumor, spleen, and thymus of mice was increased in high dose Chinese medicine group (P < 0.001). The PD1+ T cells were decreased (P < 0.001) with the increase of ubiquitination level (P < 0.01).
      CONCLUSION  Huangqi Sijunzi Decoction can upregulate the expression of CD4+and CD8+ T cells in MFC tumor bearing mice, regulate the expression level of cytokines in peripheral blood, and promote the downregulation of PD1 expression by increasing the level of intracellular ubiquitination of T cells, thus inhibiting the proliferation of gastric cancer cells.

     

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