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首页> 外文期刊>PLoS Biology >Epigenetic Reprogramming of the Type III Interferon Response Potentiates Antiviral Activity and Suppresses Tumor Growth
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Epigenetic Reprogramming of the Type III Interferon Response Potentiates Antiviral Activity and Suppresses Tumor Growth

机译：表型遗传重编程的III型干扰素反应增强抗病毒活性，并抑制肿瘤的生长。

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Type III interferon (IFN-λ) exhibits potent antiviral activity similar to IFN-α/β, but in contrast to the ubiquitous expression of the IFN-α/β receptor, the IFN-λ receptor is restricted to cells of epithelial origin. Despite the importance of IFN-λ in tissue-specific antiviral immunity, the molecular mechanisms responsible for this confined receptor expression remain elusive. Here, we demonstrate that the histone deacetylase (HDAC) repression machinery mediates transcriptional silencing of the unique IFN-λ receptor subunit (IFNLR1) in a cell-type-specific manner. Importantly, HDAC inhibitors elevate receptor expression and restore sensitivity to IFN-λ in previously nonresponsive cells, thereby enhancing protection against viral pathogens. In addition, blocking HDAC activity renders nonresponsive cell types susceptible to the pro-apoptotic activity of IFN-λ, revealing the combination of HDAC inhibitors and IFN-λ to be a potential antitumor strategy. These results demonstrate that the type III IFN response may be therapeutically harnessed by epigenetic rewiring of the IFN-λ receptor expression program.
机译：III型干扰素（IFN-λ）表现出与IFN-α/β类似的有效抗病毒活性，但与IFN-α/β受体的普遍表达相反，IFN-λ受体仅限于上皮细胞。尽管IFN-λ在组织特异性抗病毒免疫中很重要，但负责这种受限受体表达的分子机制仍然难以捉摸。在这里，我们证明了组蛋白脱乙酰基酶（HDAC）抑制机制以细胞类型特异性的方式介导了独特的IFN-λ受体亚基（IFNLR1）的转录沉默。重要的是，HDAC抑制剂可提高受体的表达并恢复以前无反应的细胞对IFN-λ的敏感性，从而增强对病毒病原体的保护。此外，阻断HDAC活性会使无反应的细胞类型易受IFN-λ促凋亡活性的影响，这表明HDAC抑制剂和IFN-λ的组合是一种潜在的抗肿瘤策略。这些结果表明，可通过表观遗传重新连接IFN-λ受体表达程序来治疗性地利用III型IFN反应。

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