Interferon-sensitive response element (ISRE) is mainly responsible for IFN-alpha-induced upregulation of programmed death-1 (PD-1) in macrophages

Cho, H-Yun.; Lee, S-Woon.; Seo, S-Kil.; Choi, I-Whan.; Choi, I.; Lee, S-Woong.

Biochimica et Biophysica Acta 1779(12): 811-819


ISSN/ISBN: 0006-3002
PMID: 18771758
DOI: 10.1016/j.bbagrm.2008.08.003
Accession: 053913220

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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.