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李师亮,方明,周彦.桂皮醛通过mTOR和STAT3调控记忆性T细胞促进心脏移植物长期存活的作用及机制研究[J].湖南中医药大学学报英文版,2023,43(3):413-420.[Click to copy
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| 桂皮醛通过mTOR和STAT3调控记忆性T细胞促进心脏移植物长期存活的作用及机制研究 |
| 李师亮,方明,周彦 |
| (华中科技大学同济医学院附属同济医院心脏大血管外科, 湖北 武汉 430030;华中科技大学同济医学院附属协和医院耳鼻咽喉头颈外科, 湖北 武汉 430022) |
| 摘要: |
| 目的 探索桂皮醛诱导记忆性心脏移植耐受的作用及潜在分子机制。方法 将60只小鼠随机分为正常对照组（假手术，n=10）、手术组（心脏移植，n=10）、模型组（注射T细胞+心脏移植，n=10）、桂皮醛低浓度组（注射T细胞+心脏移植+10 mg/kg桂皮醛，n=10）、桂皮醛中浓度组（注射T细胞+心脏移植+20 mg/kg桂皮醛，n=10）和桂皮醛高浓度组（注射T细胞+心脏移植+40 mg/kg桂皮醛，n=10）。观察各组移植物平均存活时间、移植物排斥程度，检测脾细胞增殖情况、移植物中相关基因白细胞介素-2（interleukin-2, IL-2）、白细胞介素-10（interleukin-10, IL-10）、γ-干扰素（interferon-γ, IFN-γ）和转化生长因子-β（transforming growth factor-β, TGF-β）的相对表达量，以及哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin, mTOR）与信号转导及转录激活因子3（signal transduction and activator of transcription3, STAT3）蛋白磷酸化的表达情况。结果 （1）与正常对照组相比，手术组存活时间明显缩短（P<0.05）；与手术组相比，模型组存活时间明显缩短（P<0.05）；与模型组相比，桂皮醛高浓度组的平均存活时间显著延长（P＜0.05）。（2）对各组移植物排斥程度进行评估，模型组为Ⅳ级，桂皮醛治疗组的移植物排斥程度显著降低，且具有剂量依赖性。（3）与正常对照组相比，手术组及模型组脾细胞OD值升高（P<0.05）；与模型组及桂皮醛低浓度组相比，桂皮醛中、高浓度组脾细胞OD值降低（P<0.05）。（4）与正常对照组相比，手术组IL-2、IFN-γ mRNA表达显著上调（P<0.05），IL-10、TGF-β mRNA表达显著下调（P<0.05）；与手术组相比，模型组IL-2、IFN-γ mRNA表达显著上调（P<0.05），IL-10、TGF-β mRNA表达显著下调（P<0.05）；与模型组比较，桂皮醛中、高浓度组移植物中IL-2、IFN-γ mRNA表达明显下调（P<0.05），桂皮醛中、高浓度组IL-10、TGF-β mRNA表达明显上调（P<0.05）。（5）与正常对照组相比，手术组p-mTOR、p-STAT3蛋白表达显著上调（P<0.05）；与手术组相比，模型组p-mTOR、p-STAT3蛋白表达显著上调（P<0.05）；与模型组比较，桂皮醛中、高浓度组移植物中p-mTOR、p-STAT3蛋白表达明显下调（P<0.05）。结论 对于记忆性心脏移植模型，高浓度桂皮醛可以获得移植物长期耐受，其机制可能是通过抑制mTOR和STAT3的表达，降低移植物记忆性T细胞的免疫应答水平。 |
| 关键词: 桂皮醛 记忆性T细胞 哺乳动物雷帕霉素靶蛋白 信号转导及转录激活因子3 心脏移植 |
| DOI：10.3969/j.issn.1674-070X.2023.03.008 |
| Received:June 27, 2022 |
| 基金项目:湖北省自然科学基金项目（2022030241）。 |
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| Mechanism of cinnamaldehyde in regulating long-term survival of cardiac grafts induced by memory T cells through mTOR and STAT3 |
| LI Shiliang,FANG Ming,ZHOU Yan |
| (Department of Cardiology and Vascular Surgery, Tongji Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China;Department of Otolaryngology, Head and Neck Surgery, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China) |
| Abstract: |
| Objective To explore the role of cinnamaldehyde in tolerance of memory heart transplantation as well as its potential molecular mechanism. Methods A total of 60 mice were randomly divided into normal control group (sham operation), operation group (heart transplantation), model group (T cells injection+heart transplantation), low-dose cinnamaldehyde group (T cells injection+heart transplantation+10 mg/kg cinnamaldehyde), medium-dose cinnamaldehyde group (T cells injection+heart transplantation+20 mg/kg cinnamaldehyde) and high-dose cinnamaldehyde group (T cells injection+heart transplantation+40 mg/kg cinnamaldehyde), with 10 mice in each group. The average graft survival time and graft rejection degree of each group were observed to detect the proliferation of spleen cells, the relative expression amount of interleukin-2 (IL-2), interleukin-10 (IL-10), interferon-γ (IFN-γ) and transforming growth factor-β (TGF-β), and the expression of protein phosphorylation of mammalian target of rapamycin (mTOR) and signal transduction and activator of transcription3 (STAT3) in the related genes. Results (1) Compared with normal control group, the survival time of operation group was significantly shorter (P<0.05); compared with the operation group, the survival time of the model group was also significantly shorter (P<0.05); compared with the model group, the average survival time of high-dose cinnamaldehyde group was significantly prolonged (P<0.05). (2) The degree of graft rejection in each group was scored according to the HE staining results. The score showed that the model group was grade Ⅳ, and the degree of graft rejection in cinnamaldehyde treatment group was significantly reduced in a dose-dependent manner. (3) Compared with the normal control group, the proliferation of splenocytes in operation group and model group was significantly higher (P<0.05); compared with the model and low-dose cinnamaldehyde groups, the proliferation of splenocytes in the medium- and high-dose groups was reduced (P<0.05). (4) Compared with the normal control group, the mRNA expression of IL-2 and IFN-γ in operation group was significantly up-regulated (P<0.05), while that of IL-10 and TGF-β was significantly down-regulated (P<0.05); compared with the operation group, the mRNA expression of IL-2 and IFN-γ in model group was significantly up-regulated (P<0.05), while that of IL-10 and TGF-β were significantly down-regulated (P<0.05); compared with the model group, the mRNA expression of IL-2 and IFN-γ in the medium- and high-dose groups was significantly down-regulated (P<0.05), but that of IL-10 and TGF-β genes were significantly up-regulated (P<0.05). (5) Compared with normal control group, the expression of p-mTOR and p-STAT3 proteins in operation group was significantly up-regulated (P<0.05); compared with operation group, the expression of p-mTOR and p-STAT3 protein in model group was significantly up-regulated (P<0.05); compared with model group, the expression of p-mTOR and p-STAT3 proteins in the medium- and high-dose groups was significantly down-regulated (P<0.05). Conclusion In the memory heart transplantation model, high concentration of cinnamaldehyde can achieve long-term graft tolerance, which may decrease the immune response level of graft memory T cells by inhibiting the expression of mTOR and STAT3. |
| Key words: cinnamaldehyde memory T cells mammalian target of rapamycin signal transduction and activator of transcription3 heart transplantation |
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