Interferon regulatory factor-1 is prerequisite to the constitutive expression and IFN-γ-induced upregulation of B7-H1 (CD274)
Interferon regulatory factor-1 is prerequisite to the constitutive expression and IFN-γ-induced upregulation of B7-H1 (CD274)
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DOI：
10.1016/j.febslet.2005.12.093
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发表时间：
2006-02-06
期刊：
影响因子：
3.5
通讯作者：
Choi, IH
中科院分区：
文献类型：
--
作者：
Lee, SJ;Jang, BC;Choi, IH
大多数癌细胞上调了共同抑制性分子B7-H1，该分子赋予了对抗肿瘤免疫力的耐药性，从而使癌症能够摆脱宿主的免疫监测。我们解决了响应干扰素 - 伽马（IFN-gamma）的癌症相关B7-H1表达调节的分子机制。使用荧光素酶测定中的启动子构建体，转化启动位点的202至320 bp区域负责B7-H1表达。电泳迁移率转移测定，定点诱变和使用siRNA的敲低实验表明，干扰素调节因子-1（IRF-1）主要负责本构型B7-H1表达以及IFN-GAMMA介导的B7-H1上调在人类肺癌细胞系A549中。此外，JANUS激活了激酶/信号转录器和转录抑制剂激活剂AG490，通过减少IRF-1转录，大大消除了A549细胞对IFN-GAMMA的响应性。我们的发现支持IRF-1在调节癌细胞中B7-H1表达的组成型和IFN-GAMMA诱导的表达中的关键作用。 （c）2006年欧洲生化社会联合会。由Elsevier B.V.保留所有权利。
Majority of cancer cells upregulate co-inhibitory molecule B7-H1 which confers resistance to anti-tumor immunity, allowing cancers to escape from host immune surveillance. We addressed the molecular mechanism underlying the regulation of cancer-associated B7-H1 expression in response to interferon-gamma (IFN-gamma). Using promoter constructs in luciferase assay, the region between 202 and 320 bp from the translational start site is responsible for B7-H1 expression. Electrophoretic mobility shift assay, site-directed mutagenesis and knockdown experiment using siRNA revealed that interferon regulatory factor-1 (IRF-1) is primarily responsible for the constitutive B7-H1 expression as well as for the IFN-gamma-mediated B7-H1 upregulation in a human lung cancer cell line A549. Additionally, AG490, a Janus activated kinase/signal transducer and activator of transcription inhibitor, greatly abolished the responsiveness of A549 cells to IFN-gamma by reducing the IRF-1 transcription. Our findings support a critical role of IRF-1 in the regulation of constitutive and IFN-gamma-induced expression of B7-H1 in cancer cells. (c) 2006 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.