The Promoter Context Determines Mutual Repression or Synergism between NF-κB and the Glucocorticoid Receptor

While the biochemical mechanisms mediating repression of NFκB activity by glucocorticoids (GCs) are relatively well studied, the role of promoter architecture for the effects of GCs on NFκB remains poorly characterized. Therefore we constructed a set of synthetic promoter reporter constructs containing various numbers of GCresponsive elements (GREs) in distinct distances to NFκB binding sites. TNFαinduced activity of a synthetic promoter controlled by three NFκB binding sites was repressed by dexamethasone. The presence of only one GRE in the vicinity of the κB sites abolished this repression and allowed synergistic transcriptional activation by NFκB and the glucocorticoid receptor (GR). The synergism identified here was not affected by the number of GREs, but strictly depends on the spacing between GREs and κB sites. These experiments reveal that the functional interplay between NFκB and the GR also involves dependent on the promoter context synergistic stimulation of transcription.