Glucocorticoids are anti-inflammatory factors that repress inducible gene expression dependent on the transcription factors NF-κB and AP-1. In the Proceedings of the National Academy of Science, Gupte et al. show that binding of ligand by the nuclear glucocorticoid receptor (GR) represses two classes of inflammatory signal–dependent gene transcription. GR and its corepressor GRIP1, which is recruited after ligand binding, inhibit the chromatin remodeling required by initiation-controlled genes, such as Il1a and Il1b. That action prevents recruitment of RNA polymerase II to unoccupied promoters. Additionally, GR-GRIP1 complexes block signal-dependent release by RNA polymerase II of stalled promoter-proximal complexes, including those at the Tnf and Ccl3 promoters. GR-GRIP1 prevents release of the pausing factor complex NELP and inhibits recruitment of the kinase complex P-TEFb that is required for the conversion of RNA polymerase II into elongation complexes. Thus, glucocorticoid actions target the rate-limiting steps for inflammatory gene expression.

Proc. Natl. Acad. Sci. USA (15 August 2013) doi:10.1073/pnas.1309898110