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谢小丽,张予晋,谭瑶,邓玉霞,卜佑青,钱珍珍,巴玉琛,王军文.JAK/STAT通路介导免疫缺陷大鼠CD4+T细胞分化的研究[J].湖南中医药大学学报英文版,2023,43(7):1206-1214.[Click to copy
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| JAK/STAT通路介导免疫缺陷大鼠CD4+T细胞分化的研究 |
| 谢小丽,张予晋,谭瑶,邓玉霞,卜佑青,钱珍珍,巴玉琛,王军文 |
| (湖南省中西医结合医院, 湖南 长沙 410006;湖南中医药大学第二附属医院, 湖南 长沙 410005;湖南中医药大学, 湖南 长沙 410208) |
| 摘要: |
| 目的 基于酪氨酸激酶/信号传导及转录激活蛋白（Janus kinase/signal transducer and activator of transcription，JAK/STAT）信号通路与免疫缺陷性疾病中CD4+T细胞占比减少的相关性，探讨免疫缺陷大鼠CD4+T淋巴细胞分化的机制。方法 将SPF级SD大鼠48只，随机分为正常大鼠（24只）和模型大鼠（24只），采用环孢素制备免疫缺陷模型。每组随机选6只验证造模效果，将剩余36只大鼠分为正常组、低鲁组、高鲁组、模型组、模型低鲁组、模型高鲁组，每组6只。低鲁组和模型低鲁组分别注射1.75 mg·kg-1鲁索利替尼，高鲁组和模型高鲁组分别注射3.5 mg·kg-1鲁索利替尼，正常组和模型组注射1.75 mg·kg-1生理盐水，隔日1次，共注射6次。采用流式细胞术检测CD4+T和CD8+T淋巴细胞百分比，计算大鼠脾脏和胸腺指数，HE染色法观察脾脏和胸腺病理改变，ELISA检测白细胞介素-2（interleukin-2，IL-2）、γ-干扰素（interferon-γ，IFN-γ）、白细胞介素-12（interleukin-12，IL-12）、白细胞介素-4（interleukin-4，IL-4）、白细胞介素-6（interleukin-6，IL-6）、白细胞介素-10（interleukin-10，IL-10）细胞因子表达量，Western blot检测脾脏组织中酪氨酸激酶2（Janus kinase 2，JAK2）、T盒家族转录因子表达蛋白（T-box family transcription factor expression protein，T-bet）、信号传导及转录激活蛋白4（signal transducer and activator of transcription 4，STAT4）、信号传导及转录激活蛋白6（signal transducer and activator of transcription 6，STAT6）和GATA结合蛋白-3（GATA-binding protein-3，GATA3）蛋白表达量。结果 模型组大鼠CD4+T淋巴细胞百分比、胸腺指数较正常组明显下降（P<0.05）。与正常组比较，模型组CD4+T淋巴细胞百分比减少（P<0.05），IL-2、IFN-γ和IL-12表达量下降（P<0.01），IL-10表达量升高（P<0.05）；与模型组相比，模型高鲁组CD4+T淋巴细胞百分比、胸腺和脾脏指数、IL-2、IFN-γ显著下降（P<0.05），而GATA3、STAT6蛋白表达量升高（P<0.05），IL-6、IL-10表达量明显增加（P<0.05，P<0.01）。结论 免疫缺陷疾病以CD4+T淋巴细胞减少为主要特征，CD4+T细胞亚群失调与JAK/STAT信号通路表达失衡有关，其机制可能与IL-12/STAT4通路表达下调和IL-4/STAT6通路表达上调有关，CD4+T淋巴细胞分化由辅助性T细胞1（helper T cell 1，Th1）向辅助性T细胞2（helper T cell 2，Th2）漂移，造成Th1/Th2失衡，引发免疫缺陷。 |
| 关键词: 免疫缺陷 JAK/STAT信号通路 Th1/Th2 白细胞介素-12 白细胞介素-4 信号传导及转录激活蛋白4 信号传导及转录激活蛋白6 |
| DOI：10.3969/j.issn.1674-070X.2023.07.009 |
| Received:February 16, 2023 |
| 基金项目:湖南省教育厅科学研究项目（20A382）；湖南省自然科学基金项目（2022JJ30442）；湖南中医药大学研究生创新项目（2020CX07）。 |
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| JAK/STAT pathway-mediated CD4+T cell differentiation in immunodeficient rats |
| XIE Xiaoli,ZHANG Yujin,TAN Yao,DENG Yuxia,BU Youqing,QIAN Zhenzhen,BA Yuchen,WANG Junwen |
| (Hunan Provincial Hospital of Integrated Chinese and Western Medicine, Changsha, Hunan 410006, China;The Second Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410005, China;Hunan University of Chinese Medicine, Changsha, Hunan 410208, China) |
| Abstract: |
| Objective To explore the mechanism of CD4+T lymphocyte differentiation in immunodeficient rats based on the correlation between Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway and a low percentage of CD4+T lymphocytes in immunodeficiency diseases. Methods A total of 48 SPF SD rats were randomly divided into normal group (n=24) and modeling group (n=24), and the immunodeficiency models were established using cyclosporine. Then 6 rats were randomly selected from each group to verify the modeling effects. After modeling, the remaining 18 normal rats were subdivided into normal group, low-, and high-dose ruxolitinib groups, while the remaining 18 model rats into model group, low- and high-dose ruxolitinib model groups, with 6 rats in each group. Low-dose ruxolitinib group and low-dose ruxolitinib model group were injected with 1.75 mg·kg-1 ruxolitinib, high-dose ruxolitinib group and high-dose ruxolitinib model group were injected with 3.5 mg·kg-1 ruxolitinib, while normal group and model group were injected with 1.75 mg·kg-1 normal saline, once every other day, with a total of 6 injections in each group. Then, the percentage of CD4+T and CD8+T lymphocytes was determined by flow cytometry; the spleen and thymus indexes of rats were calculated; the pathological changes of the spleen and thymus were observed by HE staining; the expression levels of interleukin-2 (IL-2), interferon-γ (IFN-γ), interleukin-12 (IL-12), interleukin-4 (IL-4), interleukin-6 (IL-6), and interleukin-10 (IL-10) were examined by ELISA; Western blot was used to check the expression levels of Janus kinase 2 (JAK2), T-box family transcription factor expression protein (T-bet), signal transducer and activator of transcription 4 (STAT4), signal transducer and activator of transcription 6 (STAT6), and GA TA-binding protein-3 (GATA3) in the spleen. Results The percentage of CD4+T lymphocytes and the thymus index in model group were significantly lower than those in normal group (P<0.05). Compared with normal group, the percentage of CD4+T lymphocytes in model group decreased (P<0.05), so did the expression levels of IL-2, IFN-γ, and IL-12 (P<0.01), but the expression level of IL-10 increased (P<0.05). Compared with model group, the percentage of CD4+T lymphocytes, the thymus and spleen indexes, and the expression levels of IL-2 and IFN-γ in high-dose ruxolitinib model group were significantly lower (P<0.05), while the expression levels of GATA3 and STAT6 proteins were higher (P<0.05) and those of IL-6 and IL-10 significantly increased (P<0.05, P<0.01). Conclusion Immunodeficiency diseases are broadly characterized by reduction in CD4+T lymphocytes, and the dysregulation of CD4+T cell subsets is related to the imbalance of JAK/STAT signaling pathway expression, with the possible mechanism of down-regulation of IL-12/STAT4 pathway expression and up-regulation of IL-4/STAT6 pathway expression. In addition, CD4+T lymphocyte differentiation drifts from helper T cell 1 (Th1) to helper T cell 2 (Th2), thus resulting in Th1/Th2 imbalance, which induces immunodeficiency. |
| Key words: immunodeficiency Janus kinase/signal transducer and activator of transcription signaling pathway helper T cell 1/helper T cell 2 interleukin-12 interleukin-4 signal transducer and activator of transcription 4 signal transducer and activator of transcription 6 |
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