Synergy between Interferon-γ and Tumor Necrosis Factor-α in Transcriptional Activation Is Mediated by Cooperation between Signal Transducer and Activator of Transcription 1 and Nuclear Factor κB

摘要: Interferon-gamma (IFNgamma) and tumor necrosis factor-alpha (TNFalpha) cooperate to induce the expression of many gene products during inflammation. The present report demonstrates that a portion this cooperativity is mediated by synergism between two distinct transcription factors: signal transducer activator 1 (STAT1) nuclear factor kappaB (NF-kappaB). IFNgamma TNFalpha synergistically mRNAs encoding interferon regulatory factor-1 (IRF-1), intercellular adhesion molecule-1, Mig (monokine induced gamma-interferon), RANTES (regulated on activation normal T cell expressed secreted) in but not STAT1-deficient mouse fibroblasts, indicating requirement for STAT1. Transient transfection assays fibroblasts using site-directed mutants 1.3-kilobase pair sequence IRF-1 promoter revealed synergy was dependent upon elements; STAT binding element motif. Artificial constructs containing single copy both motif linked herpes virus thymidine kinase were able mediate synergistic response TNFalpha; such varied with relative spacing specific regions these sites. Cooperatively responsive bound STAT1alpha NF-kappaB extracts prepared from IFNgamma- and/or TNFalpha-stimulated although individual factors cooperative. Thus, frequently observed promoting inflammatory depends part cooperation NF-kappaB, which most likely their independent interaction one or more components basal complex.