Convergence of TNF alpha and IFN gamma signalling pathways through synergistic induction of IRF-1/ISGF-2 is mediated by a composite GAS/kappa B promoter element

The molecular basis for the well known synergistic biological effects of tumor necrosis factor alpha (TNF alpha) and interferon gamma (IFN gamma) is still poorly understood. This report demonstrates that expression of interferon-regulatory factor 1 (IRF-1), also known as interferon-stimulated-gene factor 2 (ISGF-2), is synergistically induced by these cytokines. The induction is a primary transcriptional response that occurs rapidly without a requirement for new protein synthesis, Synergism is mediated by a novel composite element in the IRF-1 promoter that includes an IFN gamma-activation site (GAS) overlapped by a non-consensus site for nuclear factor kappa B (NF kappa B), These sequences are bound strongly by signal transducer and activator of transcription 1 (STAT-1) and weakly by the p50/p65 heterodimer form of NF kappa B, respectively, However, the binding of STAT-1 and NF kappa B to the GAS/kappa B element in vitro seems to be mutually exclusive and independent, Synergistic induction of IRF-1 is likely to be an important early step in regulatory networks critical to the synergism of TNF alpha and IFN gamma, The GAS/kappa B element may mediate synergistic transcriptional induction of IRF-1 by other pairs of ligands that together activate NF kappa B and STAT family members, Other genes are likely to contain this motif and be regulated similarly.