KLF4 Modulates Expression of IL-6 in Dendritic Cells via Both Promoter Activation and Epigenetic Modification*

Background: Kruppel-like factor 4 (KLF4) is a zinc finger transcription factor that influences immunity. Results: KLF4 binds to CACCC sequences in the IL-6 promoter, directly activates transcription, and impacts promoter acetylation. Conclusion: KLF4 modulates IL-6 production by dendritic cells via both a direct transcriptional activation and epigenetic modification of the promoter. Significance: KLF4 plays a significant and previously unrecognized role in regulation of IL-6. The initiation and maintenance of the immune response require a coordinated regulation of signal transduction pathways. Identifying the mechanisms by which these pathways are controlled and modulated is a significant goal of immunology. In the present report, we show a novel role for the zinc finger transcription factor Kruppel-like factor 4 (KLF4) in the modulation of the inflammatory immune response via its regulation of IL-6. We analyzed the role of KLF4 in the production of IL-6 by dendritic cells. Our data indicate that KLF4 can act in a dual function manner. It acts as a transcription factor in that it can bind to and activate the IL-6 promoter at specific binding sites. KLF4 also has a role in the chromatin remodeling of the IL-6 promoter in that cells deficient in KLF4 exhibited a relative hypoacetylation. These results indicate a molecular role for KLF4 in modulating the intensity of the inflammatory response and help to explain its pleiotropic role in different settings.

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