Context-dependent cooperation between NF-kB and the glucocorticoid receptor at a TNFAIP3 enhancer: a mechanism to maintain negative feedback control of inflammation [Molecular Bases of Disease]

February 5th, 2014 by Altonsy, M. O., Sasse, S. K., Phang, T. L., Gerber, A. N.

TNF expression is elevated in asthma and other inflammatory airway diseases that are commonly treated with glucocorticoid-based therapies, but the impact of glucocorticoids on negative feedback control of TNF is not well understood. We analyzed the effect of dexamethasone, a potent synthetic glucocorticoid, on TNF-regulated gene expression in cultured airway epithelial cells. While dexamethasone-mediated activation of the glucocorticoid receptor (GR) potently repressed expression of IL1β, IL8, and several other pro-inflammatory TNF targets, the expression of anti-inflammatory TNF targets such as TNFAIP3 and NFKBIA was selectively spared or augmented by dexamethasone treatment. Despite divergent effects on gene expression, GR and NF-kB occupancy at the TNFAIP3 locus and GR-repressed targets was similar. A co-occupied intronic TNFAIP3 regulatory element mediated cooperative enhancement of transcription by GR and NF-kB that required the presence of a functional GR binding site (GBS). GBS exchanges between reporters for TNFAIP3 and FKBP5, a canonical GR-induced target, revealed substantial latitude in the GBS sequence requirements for GR/NF-kB cooperation, suggesting that the TNFAIP3 GBS acts primarily as a docking site in this context. Supporting this notion, a selective GR ligand with only weak agonist activity for induction of FKBP5 enabled robust GR/NF-kB cooperative induction of a mutant TNFAIP3 reporter harboring the FKBP5 GBS. Taken together, our data support a model in which the expression of anti-inflammatory targets of TNF is maintained during treatment with glucocorticoids through context dependent cooperation between GR and NF-kB.
  • Posted in Journal of Biological Chemistry, Publications
  • Comments Off on Context-dependent cooperation between NF-kB and the glucocorticoid receptor at a TNFAIP3 enhancer: a mechanism to maintain negative feedback control of inflammation [Molecular Bases of Disease]