Integrated Department of Immunology, National Jewish Health, Denver, CO 80206, USA.
J Immunol. 2013 Sep 15;191(6):3384-92. doi: 10.4049/jimmunol.1203510. Epub 2013 Aug 9.
The ability of type I IFNs to increase susceptibility to certain bacterial infections correlates with downregulation of myeloid cell surface IFNGR, the receptor for the type II IFN (IFN-γ), and reduced myeloid cell responsiveness to IFN-γ. In this study, we show that the rapid reductions in mouse and human myeloid cell surface IFNGR1 expression that occur in response to type I IFN treatment reflect a rapid silencing of new ifngr1 transcription by repressive transcriptional regulators. Treatment of macrophages with IFN-β reduced cellular abundance of ifngr1 transcripts as rapidly and effectively as actinomycin D treatment. IFN-β treatment also significantly reduced the amounts of activated RNA polymerase II (pol II) and acetylated histones H3 and H4 at the ifngr1 promoter and the activity of an IFNGR1-luc reporter construct in macrophages. The suppression of IFNGR1-luc activity required an intact early growth response factor (Egr) binding site in the proximal ifngr1 promoter. Three Egr proteins and two Egr/NGFI-A binding (Nab) proteins were found to be expressed in bone macrophages, but only Egr3 and Nab1 were recruited to the ifngr1 promoter upon IFN-β stimulation. Knockdown of Nab1 in a macrophage cell line prevented downregulation of IFNGR1 and prevented the loss of acetylated histones from the ifngr1 promoter. These data suggest that type I IFN stimulation induces a rapid recruitment of a repressive Egr3/Nab1 complex that silences transcription from the ifngr1 promoter. This mechanism of gene silencing may contribute to the anti-inflammatory effects of type I IFNs.
I 型干扰素增加对某些细菌感染易感性的能力与髓系细胞表面 IFNGR 的下调相关，IFNGR 是 II 型干扰素（IFN-γ）的受体，并且降低了髓系细胞对 IFN-γ的反应性。在这项研究中，我们表明，I 型 IFN 处理后迅速减少小鼠和人髓系细胞表面 IFNGR1 表达反映了新的 ifngr1 转录的快速沉默由抑制性转录调节因子。IFN-β 处理与放线菌素 D 处理一样迅速有效地降低了巨噬细胞中 ifngr1 转录物的细胞丰度。IFN-β 处理还显著降低了激活的 RNA 聚合酶 II（pol II）和乙酰化组蛋白 H3 和 H4 在 ifngr1 启动子处的含量，以及在巨噬细胞中 IFNGR1-luc 报告基因构建体的活性。IFNGR1-luc 活性的抑制需要在近端 ifngr1 启动子中存在完整的早期生长反应因子（Egr）结合位点。在骨巨噬细胞中发现了三种 Egr 蛋白和两种 Egr/NGFI-A 结合（Nab）蛋白，但只有 Egr3 和 Nab1 在 IFN-β 刺激下被募集到 ifngr1 启动子。巨噬细胞系中 Nab1 的敲低可防止 IFNGR1 的下调，并防止乙酰化组蛋白从 ifngr1 启动子丢失。这些数据表明，I 型 IFN 刺激诱导快速募集抑制性 Egr3/Nab1 复合物，从而沉默 ifngr1 启动子的转录。这种基因沉默机制可能有助于 I 型 IFN 的抗炎作用。
