Differential interferon signaling in liver lobule and portal area cells under treatment for chronic hepatitis C
Differential interferon signaling in liver lobule and portal area cells under treatment for chronic hepatitis C
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DOI：
10.1016/j.jhep.2010.04.036
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发表时间：
2010-11-01
影响因子：
25.7
通讯作者：
Kaneko, Shuichi
中科院分区：
文献类型：
--
作者：
Honda, Masao;Nakamura, Mikiko;Kaneko, Shuichi
背景和目标：干扰素（IFN）和利巴韦林（Rib）联合治疗丙型肝炎病毒（HCV）感染的耐药机制尚不清楚。本研究的目的是深入了解这些机制，通过探索肝基因表达前和治疗过程中。方法：肝活检进行了50例患者治疗前，其中30个重复1周后开始联合治疗。结果：43例患者均为基因1型HCV感染，其中20例为病毒应答者（基因1-Rsp），治疗结果为SVR或TR，23例为无应答者（基因1-nonRsp），治疗结果为NR。只有7名患者感染了基因型2。在治疗前，IFN和Rib-stimulated基因（IRSGs），骨化相关基因，免疫反应基因途径的表达在基因型1-nonRsp比在Rsp。在治疗过程中，IRSG诱导基因型1-Rsp，但不是在nonRsp。IRSG诱导在基因型2-Rsp中不相关，主要在CLL中受损，但在CPA中不受损。通路分析显示，许多免疫调节途径诱导CLL基因型1-Rsp，而生长因子相关的血管生成和纤维化诱导CPA基因型1-nonRsp。结论：受损的IRSGs诱导CLL基因型1 HCV感染的敏感性降低治疗。肝脏中的CLL和CPA可能不同地参与治疗抗性。这些发现可能有助于改善HCV感染的治疗。(C)2010年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: The mechanisms of treatment resistance to interferon (IFN) and ribavirin (Rib) combination therapy for hepatitis C virus (HCV) infection are not known. This study aims to gain insight into these mechanisms by exploring hepatic gene expression before and during treatment.Methods: Liver biopsy was performed in 50 patients before therapy and repeated in 30 of them 1 week after initiating combination therapy. The cells in liver lobules (CLL) and the cells in portal areas (CPA) were obtained from 12 patients using laser capture microdissection (LCM).Results: Forty-three patients were infected with genotype 1 HCV, 20 of who were viral responders (genotype 1-Rsp) with treatment outcome of SVR or TR, while 23 were non-responders (genotype 1-nonRsp) with NR. Only seven patients were infected with genotype 2. Before treatment, the expression of IFN and Rib-stimulated genes (IRSGs), apoptosis-associated genes, and immune reaction gene pathways was greater in genotype 1-nonRsp than in Rsp. During treatment, IRSGs were induced in genotype 1-Rsp, but not in nonRsp. IRSG induction was irrelevant in genotype 2-Rsp and was mainly impaired in CLL but not in CPA. Pathway analysis revealed that many immune regulatory pathways were induced in CLL from genotype 1-Rsp, while growth factors related to angiogenesis and fibrogenesis were more induced in CPA from genotype 1-nonRsp.Conclusions: Impaired IRSGs induction in CLL reduces the sensitivity to treatment for genotype 1 HCV infection. CLL and CPA in the liver might be differentially involved in treatment resistance. These findings could be useful for the improvement of therapy for HCV infection. (C) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.