An essential role for NF-kappa B in IL-18-induced IFN-gamma 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 ongo ing studies on the molecular mechanisms of IL-18-induced IFN-gamma producti on, me have examined the transcriptional regulation of the IFN-gamma gene b y IL-18 in a human myelomonocytic cell line, KG-l. On the basis of DNA/prot ein binding, we have determined an IL-18-inducible NF-kappa B binding site located at -786 to -776 of the IFN-gamma gene regulatory region (designated KBBsite), Transient transfection of promoter-reporter gene constructs reve aled that the KBBsite is required for full IL-18-induced activation of the IFN-gamma gene transcription induced by IL-18, In addition, stable transfor mants of a dominant-negative form of the I kappa B alpha showed an inhibiti on of IL-18-dependent I kappa B alpha degradation, NF-kappa B activation, a nd expression of IFN-gamma, These results are the first to show the actual significance of the NF-kappa B pathway in the regulation of IFN-gamma gene expression by IL-18.