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Synergy between interferon-gamma and tumor necrosis factor-alpha in transcriptional activation is mediated by cooperation between signal transducer and activator of transcription 1 and nuclear factor kappaB

Synergy between interferon-gamma and tumor necrosis factor-alpha in transcriptional activation is mediated by cooperation between signal transducer and activator of transcription 1 and nuclear factor kappaB

Journal of Biological Chemistry 272(23): 14899-14907

Interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) cooperate to induce the expression of many gene products during inflammation. The present report demonstrates that a portion of this cooperativity is mediated by synergism between two distinct transcription factors: signal transducer and activator of transcription 1 (STAT1) and nuclear factor kappa-B (NF-kappa-B). IFN-gamma and TNF-alpha synergistically induce expression of mRNAs encoding interferon regulatory factor-1 (IRF-1), intercellular adhesion molecule-1, Mig (monokine induced by gamma-interferon), and RANTES (regulated on activation normal T cell expressed and secreted) in normal but not STAT1-deficient mouse fibroblasts, indicating a requirement for STAT1. Transient transfection assays in fibroblasts using site-directed mutants of a 1.3-kilobase pair sequence of the IRF-1 gene promoter revealed that the synergy was dependent upon two sequence elements; a STAT binding element and a kappa-B motif. Artificial constructs containing a single copy of both a STAT binding element and a kappa-B motif linked to the herpes virus thymidine kinase promoter were able to mediate synergistic response to IFN-gamma and TNF-alpha; such response varied with both the relative spacing and the specific sequence of the regions between these two sites. Cooperatively responsive sequence constructs bound both STAT1-alpha and NF-kappa-B in nuclear extracts prepared from IFN-gamma- and/or TNF-alpha-stimulated fibroblasts, although binding of individual factors was not cooperative. Thus, the frequently observed synergy between IFN-gamma and TNF-alpha in promoting inflammatory response depends in part upon cooperation between STAT1-alpha and NF-kappa-B, which is most likely mediated by their independent interaction with one or more components of the basal transcription complex.

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Accession: 009502492

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PMID: 9169460

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