Two-step model of glucocorticoid-mediated inflammatory repression. Glucocorticoids rapidly induce target genes predominantly through glucocorticoid receptor (GR) interactions with enhancers harboring canonical GR binding sites (GBSs). The consequences of genome-wide transcriptional induction by the GR include (1) an immediate early wave of repression, characterized by rapid reciprocal internucleosomal tightening at select TNF-induced enhancers that is independent of local GR occupancy, and (2) a secondary wave of repression resulting from downstream effects of genes induced by specialized enhancers subject to cooperative regulation by GR and NF-kB. These cooperatively regulated secondary effectors exert robust negative feedback control to limit further NF-kB activity and also function to counteract/destroy the various pro-inflammatory products (e.g., cytokines, chemokines, proteases) generated during the initial response, thereby playing a crucial role in promoting complete resolution of inflammation.
