摘要
目的为探讨核苷(酸)类似物(NAs)经治慢性乙型病毒性肝炎(CHB)患者干扰素α治疗过程中部分患者应答不佳的分子机制,研究干扰素信号途径中负性调控因子细胞因子信号抑制因子3(SOCS3)的表达与临床抗病毒疗效的关系。方法选取参加OSST研究的54例CHB患者的外周血和配对肝组织样本,检测不同时间点(包括基线、12周、24周、36周及48周)HBsAg定量等,观察抗病毒疗效。同时采用实时荧光定量PCR、免疫组织化学等方法检测外周血单个核细胞(PBMC)和配对肝组织(基线和48周)标本中的SOCS3的mRNA的表达水平。48周治疗结束时,出现HBsAg阴转或HBeAg血清学转换者被定义为应答组,反之为非应答组。用配对t检验比较正态分布变量;使用Mann-WhitneyU检验比较非正态分布变量组之间中位数的差异。结果在治疗48周后,聚乙二醇干扰素(Peg-IFN)组血清HBsAg水平持续下降(第48周平均下降1.14log10IU/ml,与基线相比P=0.001),而在恩替卡韦组在治疗期间几乎不变(第48周平均下降0.05log10IU/ml,与基线相比P=0.12)。Peg-IFNα-2a治疗过程中,非应答组外周血和肝组织中SOCS3的mRNA表达较应答组明显增高。肝组织免疫组织化学结果显示基线时非应答组SOCS3表达较应答组明显增强(P=0.027),在Peg-IFNα-2a治疗48周后,非应答组SOCS3的表达较基线和应答组明显增高(分别为P=0.003;P=0.012)。结论NAs经治CHB患者在干扰素α抗病毒治疗过程中,非应答组患者外周血单个核细胞以及肝组织中SOCS3的表达较应答组明显增强。推测SOCS3可能通过负性调控JAK-STAT信号通路,影响临床抗病毒疗效,部分揭示了干扰素抵抗的机制。
Objective To investigate the molecular mechanism of poor response of nucleoside and interferon therapy in some patients with chronic hepatitis B (CHB) and the negative regulatory factor of suppressor of cytokine signaling 3 (SOCS3) expression in the interferon-signaling pathway. Also, study the clinical relationship between SOCS3 and antiviral efficacy of nucleoside and interferon. Methods Peripheral blood and matched liver tissue samples from 54 CHB patients who participated in the OSST study were selected. HBsAg was measured at different time points (baseline and weeks 12, 24, 36, and 48) to observe the antiviral efficacy. Meanwhile, quantitative real-time PCR, and immunohistochemistry were used to detect the expression levels of SOCS3 mRNA in peripheral blood mononuclear cells (PBMCs) and matched liver tissues (baseline and 48 weeks). At the end of the 48-week treatment, patients with HBsAg negative or HBeAg seroconversion were defined as response group, and vice versa. Paired t-tests were used to compare normal distribution variables and the Mann-Whitney U test was used to compare the median differences between groups of non-normally distributed variables. Results After 48 weeks of treatment, serum HBsAg levels in the Peg-IFN group continued to decline (average decrease of 1.14 log10 IU / ml at week 48;P = 0.001 compared with baseline), while the entecavir group remained almost unchanged during treatment (average decrease was 0.05 log10 IU / ml at week 48;compared with baseline P = 0.12). The expression of SOCS3 mRNA (Messenger RNA, mRNA) in peripheral blood and liver tissues of non-responder group was significantly higher than the response group in the course of Peg-IFNα2a treatment. The immunohistochemical results of liver tissue showed that the expression of SOCS3 in the non-responder group was significantly higher than that in the response group at baseline (P = 0.027). After 48 weeks of treatment with Peg-IFNα2a, the expression of SOCS3 in the non-responder group was significantly higher than that in the baseline and response groups (P = 0.003, P = 0.012, respectively). Conclusion The expression of SOCS3 in peripheral blood mononuclear cells and liver tissues of non-responding CHB patients was significantly higher than that of responding CHB patients during interferon and nucleoside antiviral therapy. We speculated that SOCS3 might affect the antiviral efficacy through negative regulation of JAK-STAT signaling pathway, and partly expose the mechanism of interferon resistance.
作者
王永力
吴文煜
尤洁
严伟明
罗小平
宁琴
韩梅芳
Wang Yongli;Wu Wenyu;You Jie;Yan Weiming;Luo Xiaoping;Ning Qin;Han Meifang(Department and Institute of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China)
出处
《中华肝脏病杂志》
CAS
CSCD
北大核心
2019年第1期27-32,共6页
Chinese Journal of Hepatology
基金
十三五科技部传染病重大专项课题 (2017ZX10202201-004).
作者简介
通信作者:韩梅芳,Email:mfhan@foxmail.com.
