Interferon regulatory factor-1 is prerequisite to the constitutive expression and IFN-gamma-induced upregulation of B7-H1 (CD274).
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.
Lee
Seung-Jin
SJ
Department of Microbiology, Inje University College of Medicine, Busan 614-735, Republic of Korea.
Jang
Byeong-Churl
BC
Lee
Soo-Woong
SW
Yang
Young-Il
YI
Suh
Seong-Il
SI
Park
Yeong-Min
YM
Oh
Sangtaek
S
Shin
Jae-Gook
JG
Yao
Sheng
S
Chen
Lieping
L
Choi
In-Hak
IH
D015703:Antigens, CD; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D018122:B7-1 Antigen / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D060890:B7-H1 Antigen; D024202:Electrophoretic Mobility Shift Assay; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006367:HeLa Cells; D006801:Humans; D050856:Interferon Regulatory Factor-1 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000494:pharmacology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D016297:Mutagenesis, Site-Directed; D010455:Peptides / Q000235:genetics / Q000276:immunology; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology; D034741:RNA, Small Interfering / Q000235:genetics / Q000276:immunology / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D014158:Transcription, Genetic / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D019139:Tumor Escape / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D020032:Tyrphostins / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects* / Q000235:genetics / Q000276:immunology
D015703:Antigens, CD; D000970:Antineoplastic Agents; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D004791:Enzyme Inhibitors; D050856:Interferon Regulatory Factor-1; D008562:Membrane Glycoproteins; D010455:Peptides; D034741:RNA, Small Interfering; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D007371:Interferon-gamma; D011505:Protein-Tyrosine Kinases