Enhanced expression of suppressor of cytokine signalling‐1 in the liver of chronic hepatitis C: possible involvement in resistance to interferon therapy
Enhanced expression of suppressor of cytokine signalling‐1 in the liver of chronic hepatitis C: possible involvement in resistance to interferon therapy
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DOI：
10.1111/j.1365-2893.2005.00576.x
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发表时间：
2005-03
影响因子：
2.5
通讯作者：
K. Imanaka;Shinji Tamura;Koji Fukui;N. Ito;S. Kiso;Yasuharu Imai;T. Naka;Tadamitsu Kishimoto;Sumio Kawata;Yasuhisa Shinomura
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文献类型：
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作者：
K. Imanaka;Shinji Tamura;Koji Fukui;N. Ito;S. Kiso;Yasuharu Imai;T. Naka;Tadamitsu Kishimoto;Sumio Kawata;Yasuhisa Shinomura
总结。干扰素-α(干扰素-α)广泛应用于慢性丙型肝炎的治疗。细胞因子信号转导抑制因子(SOCS)家族参与了JAK-STAT信号的调节，包括干扰素信号。SOCS的表达对CHC对干扰素-α的应答有负面影响。应用定量逆转录聚合酶链式反应技术检测21例慢性丙型肝炎患者和8例正常对照肝脏组织中SOCS-1和SOCS-3的转录水平。我们在人肝癌细胞系PLC/PRF/5中建立了稳定表达SOCS-1的细胞系，并通过免疫印迹和Northern印迹分析了SOCS-1对干扰素-α诱导的STAT-1酪氨酸磷酸化和抗病毒基因表达的影响。对77例接受干扰素治疗的慢性丙型肝炎患者进行了SOCS-1表达与临床结局的前瞻性队列研究。慢性丙型肝炎患者肝脏中SOCS-1的转录本显著高于对照组(P<；0.005)，而SOCS-3的转录本未见表达。在SOCS-1转基因细胞中，干扰素-α诱导的STAT-1磷酸化和抗病毒基因的表达均受到抑制。肝脏SOCS-1高表达患者干扰素治疗的持续病毒学应答率显著低于SOCS-1低表达患者(P=0.0014)。与宿主因素进行的多因素分析显示，肝脏SOCS-1染色可以作为预测干扰素SVR的重要指标(P=0.004)。慢性丙型肝炎患者肝脏SOCS-1表达增强，可能参与了对干扰素治疗的抵抗。
Summary. Interferon‐α (IFN‐α) is widely used in the treatment of chronic hepatitis C (CHC). The suppressor of cytokine signalling (SOCS) family has been implicated in the regulation of JAK–STAT signalling, including IFN signalling. The negative effect of SOCS expression on the response of CHC to IFN‐α is demonstrated here. The transcriptional levels of SOCS‐1 and ‐3 in the livers of 21 patients with CHC and eight controls were investigated by quantitative reverse transcription‐polymerase chain reaction. We established stable transfectants of SOCS‐1 in a human hepatoma cell line, PLC/PRF/5 and analysed the effects of SOCS‐1 on the phosphorylation of IFN‐α‐induced STAT‐1 tyrosine by immunoblotting and the expression of antiviral genes by Northern blot. A prospective cohort study on SOCS‐1 expression and clinical outcome was carried out in 77 patients with CHC who received IFN therapy. SOCS‐1, but not SOCS‐3, transcripts in the livers of CHC were significantly higher than controls (P < 0.005). IFN‐α‐induced STAT‐1 phosphorylation and the expression of antiviral genes were inhibited in SOCS‐1‐transfected cells. Patients showing high SOCS‐1 expression in the liver had a significantly lower rate of sustained virological response (SVR) to IFN therapy than those with low SOCS‐1 expression (P = 0.0014). A multivariate analysis performed with host factors revealed that SOCS‐1 staining in the liver can serve as a significant predictor for IFN SVR (P = 0.004). SOCS‐1 expression is enhanced in the livers of CHC patients and might be involved in resistance to IFN therapy.