Dynamic expression profiling of type I and type III interferon-stimulated hepatocytes reveals a stable hierarchy of gene expression.
Dynamic expression profiling of type I and type III interferon-stimulated hepatocytes reveals a stable hierarchy of gene expression.
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DOI：
10.1002/hep.26657
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发表时间：
2014-04
期刊：
影响因子：
13.5
通讯作者：
Kleinstein, Steven H.
中科院分区：
文献类型：
--
作者：
Bolen, Christopher R.;Ding, Siyuan;Robek, Michael D.;Kleinstein, Steven H.
尽管激活了相似的信号级联，I型和III型干扰素(IFN)在对抗病毒复制的能力上有所不同。然而，目前尚不清楚这些细胞因子是否会诱导独特的抗病毒状态，特别是在肝脏中，在肝脏中，具有临床重要性的乙肝和丙型肝炎病毒会导致持续感染。在这里，基于微阵列的基因表达谱的聚类和启动子分析与信号通路的机制研究相结合，以动态地表征这些细胞因子在Huh7肝癌细胞和原代人肝细胞中诱导的转录反应。I型和III型干扰素刺激基因的诱生水平差异很大，有明显的层次结构(干扰素-β>；干扰素-α>；干扰素-λ3>；干扰素-λ1>；干扰素-λ2)。值得注意的是，尽管当使用共同的统计阈值进行量化时，该层次结构识别了不同数量的差异表达基因，但对多个时间点的基因表达的进一步分析表明，单个IFN实际上并不调节独特的基因集。除了重要的干扰素-α外，干扰素诱导的基因表达的动力学特征也是定性相似的。而干扰素-β或干扰素-λS刺激均可导致类似的长时间间歇刺激，但干扰素-α信号在刺激后提前达到峰值，然后由于负反馈机制而减弱。干扰素-α的定量表达层级和独特的动力学揭示了单个干扰素在免疫应答中潜在的特定作用，并阐明了先前观察到的干扰素抗病毒活性差异的机制。虽然目前的临床试验主要集中在干扰素-λ1作为一种潜在的抗病毒治疗上，但在III型干扰素中，干扰素-λ3总是具有最高的活性，这表明这种细胞因子可能具有更好的临床活性。
Despite activating similar signaling cascades, the type I and type III interferons (IFNs) differ in their ability to antagonize virus replication. However, it is not clear whether these cytokines induce unique antiviral states, particularly in the liver, where the clinically important hepatitis B and C viruses cause persistent infection. Here, clustering and promoter analysis of microarray-based gene expression profiling was combined with mechanistic studies of signaling pathways to dynamically characterize the transcriptional responses induced by these cytokines in Huh7 hepatoma cells and primary human hepatocytes. Type I and III IFNs differed greatly in their level of interferon-stimulated gene (ISG) induction with a clearly detectable hierarchy (IFN-β > IFN-α > IFN-λ3 > IFN-λ1 > IFN-λ2). Notably, although the hierarchy identified varying numbers of differentially expressed genes when quantified using common statistical thresholds, further analysis of gene expression over multiple time points indicated that the individual IFNs do not in fact regulate unique sets of genes. The kinetic profiles of IFN-induced gene expression were also qualitatively similar with the important exception of IFN-α. While stimulation with either IFN-β or IFN-λs resulted in a similar long-lasting ISG induction, IFN-α signaling peaked early after stimulation then declined due to a negative feedback mechanism. The quantitative expression hierarchy and unique kinetics of IFN-α reveal potential specific roles for individual IFNs in the immune response, and elucidate the mechanism behind previously observed differences in IFN antiviral activity. While current clinical trials are focused on IFN-λ1 as a potential antiviral therapy, the finding that IFN-λ3 invariably possesses the highest activity among type III IFNs suggests that this cytokine may have superior clinical activity.
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影响因子：
3.7
作者：
Pagliaccetti NE;Chu EN;Bolen CR;Kleinstein SH;Robek MD
通讯作者：
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影响因子：
3.8
作者：
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影响因子：
3.8
作者：
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通讯作者：
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影响因子：
4.1
作者：
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通讯作者：
Pellegrini, Sandra
影响因子：
4.8
作者：
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通讯作者：
tenOever, Benjamin R.