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 ongoing studies on the molecular mechanisms of IL-18-induced IFN-gamma production, we have examined the transcriptional regulation of the IFN-gamma 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-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 revealed that the KBBsite is required for full IL-18-induced activation of the IFN-gamma gene transcription induced by IL-18. In addition, stable transformants of a dominant-negative form of the I kappa B alpha showed an inhibition of IL-18-dependent I kappa B alpha degradation, NF-kappa B activation, and 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.
Kojima
H
H
Fujisaki Institute, Hayashibara Biochemical Laboratories Inc., Okayama, Japan.
Aizawa
Y
Y
Yanai
Y
Y
Nagaoka
K
K
Takeuchi
M
M
Ohta
T
T
Ikegami
H
H
Ikeda
M
M
Kurimoto
M
M
D001665:Binding Sites / Q000235:genetics / Q000276:immunology; D002461:Cell Line, Transformed; D003513:Cycloheximide / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D020672:I-kappa B Proteins; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics*; D020382:Interleukin-18 / Q000037:antagonists & inhibitors / Q000502:physiology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000276:immunology; D012045:Regulatory Sequences, Nucleic Acid / Q000276:immunology; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D020382:Interleukin-18; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D000072000:NF-KappaB Inhibitor alpha; D007371:Interferon-gamma; D004247:DNA; D003513:Cycloheximide