Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, United States of America ; Microbiology Graduate Program, Yale University School of Medicine, New Haven, Connecticut, United States of America.
Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
PLoS Biol. 2014 Jan;12(1):e1001758. doi: 10.1371/journal.pbio.1001758. Epub 2014 Jan 7.
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.
III 型干扰素 (IFN-λ) 表现出与 IFN-α/β 相似的强大抗病毒活性，但与 IFN-α/β 受体广泛表达形成鲜明对比的是，IFN-λ 受体仅限于上皮来源的细胞。尽管 IFN-λ 在组织特异性抗病毒免疫中非常重要，但负责这种受限受体表达的分子机制仍不清楚。在这里，我们证明组蛋白去乙酰化酶 (HDAC) 抑制机制以细胞类型特异性的方式介导独特的 IFN-λ 受体亚基 (IFNLR1) 的转录沉默。重要的是，HDAC 抑制剂可上调受体表达并恢复先前无反应细胞对 IFN-λ 的敏感性，从而增强对病毒病原体的保护作用。此外，阻断 HDAC 活性使无反应的细胞类型易受 IFN-λ 的促凋亡活性影响，这表明 HDAC 抑制剂和 IFN-λ 的联合使用可能是一种潜在的抗肿瘤策略。这些结果表明，通过 IFN-λ 受体表达程序的表观遗传重布线，可以对 III 型 IFN 反应进行治疗。
