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

FEBS Lett. 2006 Feb 6;580(3):755-62. doi: 10.1016/j.febslet.2005.12.093. Epub 2006 Jan 9.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, CD
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • B7-1 Antigen / biosynthesis*
  • B7-1 Antigen / genetics
  • B7-1 Antigen / immunology
  • 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
  • Interferon Regulatory Factor-1 / biosynthesis*
  • Interferon Regulatory Factor-1 / genetics
  • Interferon Regulatory Factor-1 / immunology
  • Interferon-gamma / immunology
  • Interferon-gamma / pharmacology*
  • 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 Transduction / drug effects
  • Signal Transduction / immunology
  • 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

Substances

  • Antigens, CD
  • Antineoplastic Agents
  • B7-1 Antigen
  • B7-H1 Antigen
  • CD274 protein, human
  • Enzyme Inhibitors
  • Interferon Regulatory Factor-1
  • Membrane Glycoproteins
  • Peptides
  • RNA, Small Interfering
  • Tyrphostins
  • alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
  • Interferon-gamma
  • Protein-Tyrosine Kinases