Figure 4.

A parsimonious two-part model for repression of transcription and inflammation by the glucocorticoid receptor through cross talk with NF-κB.A, first, activation of GR signaling causes rapid, primary repression of NF-κB through competition for cofactors between canonical GR:GRE complexes and a subset of NF-κB-regulated enhancers. Whether competition for factors is nucleus-wide or occurs through spatially restricted relationships between GRE and NF-κB motifs remains to be determined. B, in addition to primary repression due to competition, enhancers with GR and NF-κB binding motifs nucleate transcriptional cooperation between these two factors. GR cooperation with NF-κB exerts secondary repression through augmenting the expression of negative feedback regulators of inflammation and NF-κB (e.g., TNFAIP3, TNIP1 (142), ZC3H12A (143), IRAK3) and factors that promote inflammatory resolution and repair (e.g., BIRC3, SPHK1, SERPINA1). Although not depicted, additional induced targets of GR that appear to be regulated without NF-κB cooperation, such as TSC22D3, also contribute to secondary repression.