Interferon regulatory factor-1 is prerequisite to the constitutive expression and IFN-γ-induced upregulation of B7-H1 (CD274)

• Published in: FEBS letters 2006-02, Vol.580 (3), p.755-762
• Main Authors: Lee, Seung-Jin, Jang, Byeong-Churl, Lee, Soo-Woong, Yang, Young-Il, Suh, Seong-Il, Park, Yeong-Min, Oh, Sangtaek, Shin, Jae-Gook, Yao, Sheng, Chen, Lieping, Choi, In-Hak
• Format: Article
• Language: English
• Subjects: Antigens, CD; Antineoplastic Agents - metabolism; Antineoplastic Agents - pharmacology; B7-1 Antigen - biosynthesis; B7-1 Antigen - genetics; B7-1 Antigen - immunology; B7-H1; B7-H1 Antigen; Electrophoretic Mobility Shift Assay; Enzyme Inhibitors - pharmacology; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; Gene Expression Regulation, Neoplastic - immunology; HeLa Cells; Humans; IFN-γ; interferon regulatory factor-1; Interferon Regulatory Factor-1 - biosynthesis; Interferon Regulatory Factor-1 - genetics; Interferon Regulatory Factor-1 - immunology; Interferon-gamma - immunology; Interferon-gamma - pharmacology; interferon-γ; IRF-1; JAK; JAK/STAT pathway; Janus activated kinase; Membrane Glycoproteins - biosynthesis; Membrane Glycoproteins - genetics; Membrane Glycoproteins - immunology; Mutagenesis, Site-Directed; Peptides - genetics; Peptides - immunology; Promoter Regions, Genetic - genetics; Promoter Regions, Genetic - immunology; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - immunology; RNA, Small Interfering - genetics; RNA, Small Interfering - immunology; RNA, Small Interfering - pharmacology; signal transducer and activator of transcription; Signal Transduction - drug effects; Signal Transduction - immunology; STAT; Transcription, Genetic - drug effects; Transcription, Genetic - genetics; Transcription, Genetic - immunology; Tumor Escape - drug effects; Tumor Escape - genetics; Tumor Escape - immunology; Tyrphostins - pharmacology; Up-Regulation - drug effects; Up-Regulation - genetics; Up-Regulation - immunology
• ISSN: 0014-5793; 1873-3468
• DOI: 10.1016/j.febslet.2005.12.093

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-γ (IFN-γ). Using promoter constructs in luciferase assay, the region between 202 and 320bp 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-γ-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-γ by reducing the IRF-1 transcription. Our findings support a critical role of IRF-1 in the regulation of constitutive and IFN-γ-induced expression of B7-H1 in cancer cells.