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Enhancer role of STAT5 in CD2 activation of IFN-gamma gene expression

  1. Author:
    Gonsky, R.
    Deem, R. L.
    Bream, J.
    Young, H. A.
    Targan, S. R.
  2. Author Address

    Cedars Sinai Med Ctr, Inflammatory Bowel Dis Res Ctr, Los Angeles, CA 90048 USA. NIAMSD, Lymphocyte Cell Biol Sect, Mol Immunol & Inflammat Branch, Intramural Res Program,NIH, Bethesda, MD 20892 USA. NCI, Cellular & Mol Immunol Sect, Expt Immunol Lab, Frederick, MD 21702 USA Targan, SR, Cedars Sinai Med Ctr, Inflammatory Bowel Dis Res Ctr, 8700 Beverly Blvd,D4063, Los Angeles, CA 90048 USA
    1. Year: 2004
    2. Date: NOV 15
  1. Journal: Journal of Immunology
    1. 173
    2. 10
    3. Pages: 6241-6247
  2. Type of Article: Article
  1. Abstract:

    IFN-gamma is an important immunoregulatory protein with tightly controlled expression in activated T and NK cells. Three potential STAT binding regions have been recognized within the IFN-gamma promoter: 1) an IL-12-mediated STAT4 binding site at -236 bp; 2) a newly identified IL-2-induced STAT5 binding element at -3.6 kb; and 3) CD2-mediated STAT1 and STAT4 binding to an intronic element in mucosal T cells. However, functional activation of these sites remains unclear. In this study we demonstrate CD2-mediated activation of the newly characterized -3.6-kb IFN-gamma STAT5 binding region. CD2 signaling of human PBMC results in activation of the -3.6-kb IFN-gamma promoter, whereas mutation of the -3.6-kb STAT5 site attenuates promoter activity. Functional activation is accompanied by STAT5A but little STAT513 nucleoprotein binding to the IFN-gamma STAT5 site, as determined by competition and supershift assays. STAT5 activation via CD2 occurs independent of IL-2. Western and FACS analysis shows increased phospho-STAT5 following CD2 signaling. AG490, a tyrosine kinase inhibitor affecting Jak proteins, inhibits CD2-mediated IFN-gamma mRNA expression, secretion, and nucleoprotein binding to the IFN-gamma STAT5 site in a dose-dependent fashion. This report is the first to describe CD2-mediated activation of STAT5 and supports STAT5 involvement in regulation of IFN-gamma expression

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External Sources

  1. WOS: 000224999000042

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