| Cytokine initiation of inflammation is a critical aspect of the immune response. Monocytes encountering pathogen-associated molecular patterns in the microenvironment are among the first cells to respond to infection by producing cytokines. Two monocyte derived cytokines are TNF-alpha and IL-23. TNF-alpha acts on almost every cell type while IL-23 specifically stimulates T cells and NK cells to produce IL-17. Regulation of expression of these two cytokines is critically important. Initiation of transcription is controlled both by the activation of gene specific transcription factors, but also ordered chromatin remodeling to render gene promoters accessible to transcription factors. We show here that IFN-gamma increases histone acetylation of the TNF-alpha promoter and increases TNF-alpha production. Additionally, IFN-gamma polarization alone is enough to acetylate histone 4, phosphorylate ATF2, recruit ATF2 via p38 signaling, and recruit RNA Pol II to the TNF-alpha promoter in response to ERK signaling. For IL-23 p19, we identified a nucleosome located at -601 to -521 of the promoter. This nucleosome underwent histone modifications in response to TLR ligand stimulation. Understanding the transcriptional regulation of inflammatory cytokines may provide unique targets for clinical therapeutics. |
