Interferon-sensitive response element (ISRE) is mainly responsible for IFN-α-induced upregulation of programmed death-1 (PD-1) in macrophages
Interferon-sensitive response element (ISRE) is mainly responsible for IFN-α-induced upregulation of programmed death-1 (PD-1) in macrophages
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DOI：
10.1016/j.bbagrm.2008.08.003
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发表时间：
2008-12-01
影响因子：
4.7
通讯作者：
Lee, Soo-Woong
中科院分区：
文献类型：
--
作者：
Cho, Hae-Yun;Lee, Soo-Woon;Lee, Soo-Woong
程序性死亡-1（PD-1）是一种免疫抑制受体，激活后在T细胞、B细胞、NKT细胞和单核细胞中上调。更具体地，T细胞相关PD-1对于通过PD-1-B7-H1途径维持外周耐受性至关重要。然而，巨噬细胞相关PD-1的生理作用仍不清楚。我们探讨了IFN-α对巨噬细胞PD-1表达调节的分子机制。基于使用启动子构建体的荧光素酶测定，我们发现位于距翻译起始位点-1090和-1105个核苷酸之间的启动子区域对于PD-1表达是必需的。电泳迁移率变化分析和定点突变显示，干扰素敏感反应元件（ISRE）和STAT 1和STAT 2主要负责PD-1的组成型表达，以及IFN-α介导的PD-1上调。此外，AG 490，Janus激活的激酶/信号转导和转录激活因子（JAK/STAT）抑制剂，显着消除骨髓来源的巨噬细胞（BMM）的IFN-α的反应性。我们的研究结果支持ISRE，STAT 1和STAT 2在巨噬细胞中组成性和IFN-α介导的PD-1表达的调节中的重要作用。(C)2008 Elsevier B. V.保留所有权利。
Programmed death-1 (PD-1), an immunoinhibitory receptor, is upregulated in T cells, B cells, NKT cells, and monocytes upon activation. More specifically, T-cell-associated PD-1 is critically important for maintaining peripheral tolerance through the PD-1-B7-H1 pathway. However, the physiological role of macrophage-associated PD-1 remains unclear. We addressed the molecular mechanism underlying the regulation of PD-1 expression on macrophages in response to IFN-alpha. Based on a luciferase assay using promoter constructs, we found that the promoter region located between -1090 and -1105 nucleotides from the translational start site is essential for PD-1 expression. Electrophoretic mobility-shift assay and site-directed mutagenesis revealed that interferon-sensitive responsive element (ISRE) and STAT1 and STAT2 are primarily responsible for the constitutive expression of PD-1, as well as for the IFN-alpha-mediated upregulation of PD-1. In addition, AG490, a Janus-activated kinase/signal transducer and activator of transcription (JAK/STAT) inhibitor, markedly abolished the responsiveness of bone marrow-derived macrophages (BMM) to IFN-alpha. Our findings support the essential roles of ISRE, STAT1, and STAT2 in the regulation of constitutive and IFN-alpha-mediated PD-1 expression in macrophages. (C) 2008 Elsevier B.V. All rights reserved.