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IL-12 逆转顺铂对人NK细胞免疫功能的抑制及其机制[J].沈娟,吴琼丽,杨滨燕,吴长有.中国肿瘤生物治疗杂志,2018,(9):872~877.
IL-12 逆转顺铂对人NK细胞免疫功能的抑制及其机制    点此下载全文    点此浏览HTML全文
沈娟  吴琼丽  杨滨燕  吴长有
中山大学中山医学院免疫学研究所广东省器官移植重点实验室,广东广州 510080
基金项目:国家自然科学基金资助项目(No.31470888)
DOI:10.3872/j.issn.1007-385X.2018.09.005
摘要:
      目的: 探讨IL-12 逆转化疗药物对NK细胞免疫功能的抑制及其机制。方法: 纯化的NK细胞在PMA和Ionomycin刺激条件下、加或不加化疗药物顺铂(cisplatin,DDP)和IL-12,用ELISA法检测培养上清中IFN-γ 和TNF-α 的分泌水平,流式细胞术检测IFN-γ 和TNF-α、肿瘤坏死因子相关的凋亡诱导配体(TNF-related apoptosis inducing ligand, TRAIL)和转录因子(T-bet 和p-STAT-4)的表达百分率;纯化NK细胞加或不加化疗药物和IL-12 预处理48 h,流式细胞术检测其对白血病Jurkat 细胞株的杀伤效应。结果: 化疗药物明显抑制NK细胞分泌IFN-γ、TNF-α 以及TRAIL 的表达,IL-12 可以明显逆转DDP对NK细胞分泌IFN-γ、TNF-α 和TRAIL 的抑制(P<0.05 或P<0.01)。DDP抑制IFN-γ 和TNF-α 的转录因子p-STAT-4 的表达,而IL-12 通过上调磷酸化STAT-4 恢复了NK细胞的IFN-γ 和TNF-α 的分泌功能(P<0.01)。杀伤实验显示,DDP抑制NK细胞对白血病细胞Jurkat 的杀伤,而IL-12 通过上调TRAIL恢复NK细胞的杀伤功能(P<0.05 或P<0.01)。结论: 化疗药物DDP抑制NK细胞的杀伤功能以及细胞因子(IFN-γ 和TNF-α)的分泌,IL-12 通过上调TRAIL和转录因子STAT-4 的磷酸化恢复NK细胞的免疫功能,为临床应用IL-12 重建肿瘤化疗患者的免疫功能提供实验依据。
关键词:NK细胞;顺铂;IL-12;免疫抑制  Jurkat细胞株
IL-12 reverses inhibitory effect of cisplatin on immune function of human NK cells and its mechanism    Download Fulltext
SHEN Juan  WU Qiongli  YANG Binyan  WU Changyou
Institute of Immunology, Key Laboratory of Organ Donation and Transplant Immunology of Guangdong Provincial, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510080, Guangdong,China
Fund Project:Project supported by the National Natural Science Foundation of China (No.31470888)
Abstract:
      Objective: To investigate the reverse effect and mechanism of IL-12 on chemotherapeutic medicine suppressing the immune function of NK cells. Methods: Purified NK cells were stimulated with PMA plus Ionomycin in the presence or absent of Cisplatin (DDP) and IL-12. The levels of IFN- γ and TNF- α in culture supernatants were detected by enzyme-linked immunosorbent assay (ELISA); The content of IFN-γ and TNF-α, TRAIL (TNF-related apoptosis inducing ligand) and transcription factors including T-bet and p-STAT-4 in NK cells were analyzed by Flow cytometry. The cytotoxicity of purified NK cells (pretreated with/without chemotherapeutics and IL-12 for 48 h) to Jurkat cells was measured by Flow cytometry. Results: Chemotherapeutics significantly inhibited the production of IFN-γ, TNF-α and the expression of TRAIL in NK cells, which were significantly reversed by IL-12 (P<0.05 or P<0.01). Further study revealed that chemotherapeutics down-regulated while IL-12 reversed the expression of p-STAT4 to restore cytokine production.In addition, DDP also inhibited but IL-12 recovered the cytotoxicity of NK cells against tumor cells by inducing the expression of TRAIL (P<0.05 or P<0.01). Conclusion: Chemotherapeutics inhibited the cytotoxicity of NK cells and its secretion of cytokines (IFN-γ and TNF-α), which were reversed by IL-12 via up-regulating TRAIL and p-STAT-4; this might provide experimental evidence for the clinical application of IL-12 for rebuild the immune function of tumor patients receiving chemotherapy.
Keywords:NK cell  DDP  IL-12  immune suppression  Jurkat cell line
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