An Essential Role for NF-κB in IL-18-Induced IFN-γ Expression in KG-1 Cells

IL-18 is a multifunctional cytokine playing various regulatory roles in the immune system including induced cytokine production. As a part of our ongoing studies on the molecular mechanisms of IL-18-induced IFN-γ production, we have examined the transcriptional regulation of the IFN-γ gene by IL-18 in a human myelomonocytic cell line, KG-1. On the basis of DNA/protein binding, we have determined an IL-18-inducible NF-κB binding site located at −786 to −776 of the IFN-γ gene regulatory region (designated KBBsite). Transient transfection of promoter-reporter gene constructs revealed that the KBBsite is required for full IL-18-induced activation of the IFN-γ gene transcription induced by IL-18. In addition, stable transformants of a dominant-negative form of the IκBα showed an inhibition of IL-18-dependent IκBα degradation, NF-κB activation, and expression of IFN-γ. These results are the first to show the actual significance of the NF-κB pathway in the regulation of IFN-γ gene expression by IL-18.