Synergistic activation of intercellular adhesion molecule 1 (ICAM-1) by TNF-alpha and IFN-gamma is mediated by p65/p50 and p65/c-Rel and interferon-responsive factor Stat1 alpha (p91) that can be activated by both IFN-gamma and IFN-alpha.
Human ICAM-1 expression is up-regulated by IFN-gamma and TNF-alpha and synergistically increased by a combination of both. Transient expression of ICAM-1/luciferase constructs led to definition of the regulatory regions mediating the cytokine response and showed that both are necessary for synergism. Immunochemical electromobility shift assays identified the TNF-alpha-dependent complexes that bound to the NF-kappa B like sequence at -187 as p65/p50 and p65/c-Rel. The interferon responsive region at -75 was bound by a Stat1 alpha (p91) containing complex that was activated by both IFN-gamma and IFN-alpha. Although both regions were required for synergism, no additional or enhanced binding complexes were observed.
Institute of Immunology, Munich, Germany.
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Jahnke
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JP
Johnson
D001483:Base Sequence; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004357:Drug Synergism; D005455:Fluorescent Antibody Technique; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D016898:Interferon-alpha / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D008156:Luciferases / Q000235:genetics; D008545:Melanoma; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020569:Proto-Oncogene Proteins c-rel; D012333:RNA, Messenger / Q000378:metabolism; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D012045:Regulatory Sequences, Nucleic Acid; D050794:STAT1 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D020569:Proto-Oncogene Proteins c-rel; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D007371:Interferon-gamma; D008156:Luciferases