The nuclear factor-kappa B engages CBP/p300 and histone acetyltransferase activity for transcriptional activation of the interleukin-6 gene promoter

Expression of the pleiotropic cytokine interleukin (IL)-6 can be stimulated by the proinflammatory cytokine tumor necrosis factor (TNF) and the microb ial alkaloid staurosporine (STS). In this report, the transcriptional mecha nisms were thoroughly investigated. Whereas transcription factors binding t o the activator protein-1-, cAMP-responsive element-, and CAAT enhancer-bin ding protein-responsive sequences are necessary for gene activation by STS, nuclear factor (NF)-kappa B alone is responsible and sufficient for induci bility by TNF, which reveals distinct signaling pathways for both compounds . At the cofactor level, cAMP-responsive element-binding protein-binding pr otein (CBP) or p300 potentiate basal and induced IL-6 promoter activation v ia multiple protein-protein interactions with all transcription factors bou nd to the promoter DNA. However, the strongest promoter activation relies o n the p65 NF-kappa B subunit, which specifically engages CBP/p300 for maxim al transcriptional stimulation by its histone acetyltransferase activity. M oreover, treatment of chromatin-integrated promoter constructions with the histone deacetylase inhibitor trichostatin A exclusively potentiates TNF-de pendent (ie. NF-kappa B-mediated) gene activation, while basal or STS-stimu lated IL-6 promoter activity remains completely unchanged. Similar observat ions were recorded with other natural NF-kappa B-driven promoters, namely I L-8 and endothelial leukocyte adhesion molecule (ELAM). We conclude that, w ithin an "enhanceosome-like" structure, NF-kappa B is the central mediator of TNF-induced IL-6 gene expression, involving CBP/p300 and requiring histo ne acetyltransferase activity.