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Context-dependent cooperation between nuclear factor ?B (NF-?B) and the glucocorticoid receptor at a TNFAIP3 intronic enhancer: a mechanism to maintain negative feedback control of inflammation.

ABSTRACT: 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. Although dexamethasone-mediated activation of the glucocorticoid receptor (GR) potently repressed expression of IL1?, IL8, and several other pro-inflammatory TNF targets, the expression of anti-inflammatory TNF targets such as TNFAIP3 (A20) and NFKBIA was selectively spared or augmented by dexamethasone treatment. Despite divergent effects on gene expression, GR and NF-?B 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-?B 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-?B 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-?B 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-?B.

SUBMITTER: Altonsy MO

PROVIDER: S-EPMC3961651 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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Context-dependent cooperation between nuclear factor κB (NF-κB) and the glucocorticoid receptor at a TNFAIP3 intronic enhancer: a mechanism to maintain negative feedback control of inflammation.

Altonsy Mohammed O MO Sasse Sarah K SK Phang Tzu L TL Gerber Anthony N AN

The Journal of biological chemistry 20140205 12

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. Although dexamethasone-mediated activation of the glucocorticoid receptor (GR) potently repressed expression of IL1β, IL8 ...[more]

PMID: 24500711

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Project description:OBJECTIVE:Although often studied independently, little is known about how aortic valve endothelial cells and valve interstitial cells interact collaborate to maintain tissue homeostasis or drive valve calcific pathogenesis. Inflammatory signaling is a recognized initiator of valve calcification, but the cell-type-specific downstream mechanisms have not been elucidated. In this study, we test how inflammatory signaling via NF?B (nuclear factor ?-light-chain enhancer of activated B cells) activity coordinates unique and shared mechanisms of valve endothelial cells and valve interstitial cells differentiation during calcific progression. Approach and Results: Activated NF?B was present throughout the calcific aortic valve disease (CAVD) process in both endothelial and interstitial cell populations in an established mouse model of hypercholesterolemia-induced CAVD and in human CAVD. NF?B activity induces endothelial to mesenchymal transformation in 3-dimensional cultured aortic valve endothelial cells and subsequent osteogenic calcification of transformed cells. Similarly, 3-dimensional cultured valve interstitial cells calcified via NF?B-mediated osteogenic differentiation. NF?B-mediated endothelial to mesenchymal transformation was directly demonstrated in vivo during CAVD via genetic lineage tracking. Genetic deletion of NF?B in either whole valves or valve endothelium only was sufficient to prevent valve-specific molecular and cellular mechanisms of CAVD in vivo despite the persistence of a CAVD inducing environment. CONCLUSIONS:Our results identify NF?B signaling as an essential molecular regulator for both valve endothelial and interstitial participation in CAVD pathogenesis. Direct demonstration of valve endothelial cell endothelial to mesenchymal transformation transmigration in vivo during CAVD highlights a new cellular population for further investigation in CAVD morbidity. The efficacy of valve-specific NF?B modulation in inhibiting hypercholesterolemic CAVD suggests potential benefits of multicell type integrated investigation for biological therapeutic development and evaluation for CAVD.

Dataset Information

Context-dependent cooperation between nuclear factor ?B (NF-?B) and the glucocorticoid receptor at a TNFAIP3 intronic enhancer: a mechanism to maintain negative feedback control of inflammation.

Publications

Context-dependent cooperation between nuclear factor κB (NF-κB) and the glucocorticoid receptor at a TNFAIP3 intronic enhancer: a mechanism to maintain negative feedback control of inflammation.

Similar Datasets

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