New insight into the enhanced effect of pegylated interferon-α.
New insight into the enhanced effect of pegylated interferon-α.
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关于聚乙二醇化干扰素-α 增强作用的新见解。
DOI：
10.1002/hep.27269
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Chayama K.
中科院分区：
文献类型：
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作者：
Abe H;Hayes CN;Chayama K.
聚乙二醇化干扰素-α(PEGIFN-α)已取代未经修饰的重组干扰素-α用于治疗慢性病毒性肝炎。虽然PEGIFN-α的优越抗病毒效果通常归因于改善的药代动力学特性，但PEGIFN-α在肝脏中的药效学效应尚未被研究。在这里，我们分析了18例慢性丙型肝炎患者在治疗前和注射PEG干扰素-α后第一周内获得的配对肝活检组织中PEG干扰素-α诱导的信号和基因调节。尽管血清中持续存在高浓度的PEGIFN-α，但只有在注射PEGIFN-α后的第一天，肝细胞中的JAK/STAT通路才被激活。对肝活检组织的评估表明，PEGIFN-α诱导了成百上千个基因，根据不同的时间表达谱可将其归类为四个簇。在所有簇中，基因转录主要由干扰素刺激的基因因子3(ISGF3)驱动。与传统的干扰素-α治疗相比，α诱导的基因表达谱更广，包括许多与细胞免疫有关的基因。干扰素诱导的次级转录因子不会导致额外的基因表达波。我们的数据表明，PEGIFN-α的优越抗病毒效果不是由于肝细胞中JAK/STAT通路的延长激活，而是由于诱导了参与细胞免疫反应的额外基因。
The use of pegylated interferon-α (pegIFN-α) has replaced unmodified recombinant IFN-α for the treatment of chronic viral hepatitis. While the superior antiviral efficacy of pegIFN-α is generally attributed to improved pharmacokinetic properties, the pharmacodynamic effects of pegIFN-α in the liver have not been studied. Here, we analyzed pegIFN-α-induced signaling and gene regulation in paired liver biopsies obtained prior to treatment and during the first week following pegIFN-α injection in 18 patients with chronic hepatitis C. Despite sustained high concentrations of pegIFN-α in serum, the Jak/STAT pathway was activated in hepatocytes only on the first day after pegIFN-α administration. Evaluation of liver biopsies revealed that pegIFN-α induces hundreds of genes that can be classified into four clusters based on different temporal expression profiles. In all clusters, gene transcription was mainly driven by IFN-stimulated gene factor 3 (ISGF3). Compared with conventional IFN-α therapy, pegIFN-α induced a broader spectrum of gene expression, including many genes involved in cellular immunity. IFN-induced secondary transcription factors did not result in additional waves of gene expression. Our data indicate that the superior antiviral efficacy of pegIFN-α is not the result of prolonged Jak/STAT pathway activation in hepatocytes, but rather is due to induction of additional genes that are involved in cellular immune responses.