Pegylated IFN-α regulates hepatic gene expression through transient Jak/STAT activation
Pegylated IFN-α regulates hepatic gene expression through transient Jak/STAT activation
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DOI：
10.1172/jci70408
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发表时间：
2014-04-01
影响因子：
15.9
通讯作者：
Heim, Markus H.
中科院分区：
文献类型：
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作者：
Dill, Michael T.;Makowska, Zuzanna;Heim, Markus H.
聚乙二醇化干扰素-α（pegIFN-α）的使用已取代未修饰的重组IFN-α用于治疗慢性病毒性肝炎。虽然pegIFN-α的上级抗病毒功效通常归因于改善的药代动力学特性，但尚未研究pegIFN-α在肝脏中的药效学效应。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pegIFN-α后第一周获得的成对肝活检中pegIFN-α诱导的信号传导和基因调控。尽管血清中持续存在高浓度的pegIFN-α，但Jak/STAT途径仅在pegIFN-α给药后第一天在肝细胞中激活。肝活检的评估显示，pegIFN-α诱导数百个基因，这些基因可以根据不同的时间表达谱分为四个簇。在所有簇中，基因转录主要由IFN刺激的基因因子3（ISGF 3）驱动。与传统的IFN-α治疗相比，pegIFN-α诱导了更广泛的基因表达，包括许多参与细胞免疫的基因。IFN诱导的次级转录因子没有导致额外的基因表达波。我们的数据表明，pegIFN-α的上级抗病毒疗效不是肝细胞中Jak/STAT途径激活延长的结果，而是由于诱导了参与细胞免疫应答的其他基因。
The use of pegylated interferon-alpha (pegIFN-alpha) has replaced unmodified recombinant IFN-alpha for the treatment of chronic viral hepatitis. While the superior antiviral efficacy of pegIFN-alpha is generally attributed to improved pharmacokinetic properties, the pharmacodynamic effects of pegIFN-alpha in the liver have not been studied. Here, we analyzed pegIFN-alpha-induced signaling and gene regulation in paired liver biopsies obtained prior to treatment and during the first week following pegIFN-alpha injection in 18 patients with chronic hepatitis C. Despite sustained high concentrations of pegIFN-alpha in serum, the Jak/STAT pathway was activated in hepatocytes only on the first day after pegIFN-alpha administration. Evaluation of liver biopsies revealed that pegIFN-alpha 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-alpha therapy, pegIFN-alpha 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-alpha 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.