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Notch信号通路对慢性丙型肝炎患者CD8+T淋巴细胞功能的影响
Influence of the Notch signaling pathway on CD8+ T lymphocyte function in patients with chronic hepatitis C
文章发布日期:2018年01月05日  来源:  作者:李彧,张鸿,李竹,等  点击次数:700次  下载次数:120次

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【摘要】:目的观察Notch信号通路对慢性丙型肝炎患者CD8+T淋巴细胞功能的影响,初步阐释Notch信号通路在慢性丙型肝炎发病中的作用。方法收集2016年1月-8月在陕西省人民医院就诊的慢性丙型肝炎初治患者38例和健康志愿者17例,分选CD8+T淋巴细胞,应用实时定量PCR法检测CD8+T淋巴细胞中Notch1和Notch2 mRNA的表达水平。分别应用直接接触培养系统和间接接触培养系统将从HLA-A2限制性丙型肝炎患者分选的CD8+T淋巴细胞与HCV感染的Huh7.5细胞共培养,加入Notch信号通路抑制剂DAPT,通过检测乳酸脱氢酶和细胞因子水平分析CD8+T淋巴细胞的细胞毒性和非细胞毒性功能的变化。2组间计量资料的比较采用t检验。结果Notch1和Notch2 mRNA在慢性丙型肝炎患者CD8+T淋巴细胞中的表达水平较健康志愿者均显著升高,分别升高约10倍和4倍,差异均有统计学意义(t值分别为6.63、18.88,P值分别为0.003、<0.001)。抑制Notch信号通路可增加直接接触培养系统中细胞死亡的比例[(26.41±4.76)% vs (13.65±4.65)%,t=3.32,P=0.029];但抑制Notch信号通路对间接接触培养细胞中CD8+T淋巴细胞毒性无明显影响。抑制Notch信号通路后,IFNγ的表达在直接接触培养系统[(52.19±12.38) pg/ml vs(18.62±5.66) pg/ml,t=4.27,P=0.013]和间接接触培养系统[(18.86±3.09)pg/ml vs (5.52±2.52) pg/ml,t=5.79,P=0.004]中均显著升高。TNF α的表达在抑制Notch信号通路后仅在直接接触培养系统中显著升高[(1296.0±293.3) pg/ml vs(585.3±32.62) pg/ml,t=4.17,P=0.014],而在间接接触培养系统中无明显变化[(297.3±175.4)pg/ml vs (273.7±105.9)pg/ml,t=020,P=0.851]。结论抑制Notch信号通路可增强慢性丙型肝炎患者中CD8+T淋巴细胞的细胞杀伤和非细胞杀伤功能,Notch信号通路在慢性HCV感染中可能通过抑制CD8+T淋巴细胞功能发挥诱导免疫耐受的作用。
【Abstract】:ObjectiveTo investigate the influence of the Notch signaling pathway on CD8+ T lymphocyte function in patients with chronic hepatitis C (CHC) and the role of the Notch signaling pathway in the pathogenesis of CHC. MethodsA total of 38 treatment-nave CHC patients who visited Shaanxi Provincial People′s Hospital from January to August, 2016 and 17 healthy volunteers were enrolled in this study. CD8+ T lymphocytes were isolated, and quantitative real-time PCR was used to measure the mRNA expression of Notch1 and Notch2 in CD8+ T lymphocytes. CD8+T lymphocytes, which were isolated from HLA-A2-restricted CHC patients, were co-cultured with hepatitis C virus (HCV)-infected Huh7.5 cells in both direct and indirect contact culture systems. DAPT, a Notch signaling pathway inhibitor, was added, and the changes in cytotoxic and non-cytotoxic functions of CD8+T lymphocytes were analyzed by measuring the levels of lactate dehydrogenase level and cytokines. The t-test was used for comparison of continuous data between groups. ResultsThe mRNA expression of Notch1 and Notch2 in CD8+ T lymphocytes in CHC patients was 10 and 4 times, respectively, that in healthy volunteers (t=6.63, P=0.003; t=18.88, P<0.001). Inhibition of the Notch signaling pathway significantly increased the percentage of dead cells in the direct contact culture system (26.41±4.76% vs 13.65±4.65%, t=3.32, P=0.029), while it did not influence the cytotoxity of CD8+T lymphocytes in the indirect contact culture system. After inhibition of the Notch signaling pathway, there was a significant increase in the expression of interferon-γ in the direct (52.19±12.38 pg/ml vs 18.62±5.66 pg/ml, t=4.27, P=0.013) and indirect contact culture systems (18.86±3.09 pg/ml vs 5.52±2.52 pg/ml, t=5.79, P=0.004). After inhibition of the Notch signaling pathway, there was a significant increase in the expression of tumor necrosis factor-α in the direct contact culture system (1296.0±293.3 pg/ml vs 585.3±32.62 pg/ml, t=4.17, P=0.014), while there was no significant change in the indirect contact culture system (297.3±175.4 pg/ml vs 273.7±105.9 pg/ml, t=0.20, P=0.851). ConclusionInhibition of the Notch signaling pathway can enhance the cytotoxic and non-cytotoxic functions of CD8+T lymphocytes in CHC patients. The Notch signaling pathway may induce immune tolerance in chronic HCV infection by inhibiting the function of CD8+ T lymphocytes.
【关键字】:肝炎, 丙型, 慢性; CD8阳性T淋巴细胞; 信号传导
【Key words】:hepatitis C, chronic; CD8-positive T-lymphocytes; signal transduction
【引证本文】:LI Y, ZHANG H, LI Z, et al. Influence of the Notch signaling pathway on CD8+ T lymphocyte function in patients with chronic hepatitis C[J]. J Clin Hepatol, 2018, 34(2): 287-291. (in Chinese)
李彧, 张鸿, 李竹, 等. Notch信号通路对慢性丙型肝炎患者CD8+T淋巴细胞功能的影响[J]. 临床肝胆病杂志, 2018, 34(2): 287-291.

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