Selective modulation of the glucocorticoid receptor can distinguish between transrepression of NF-κB and AP-1

Karolien De Bosscher,Guy Haegeman,Jan Tavernier,Anthoula Gaigneaux,Marc Bracke,Marc Diederich,Ilse M Beck,Nadia Bougarne,Wim Vanden Berghe,Dariusz Ratman,Sébastien Chateauvieux,Lien Dejager,Claude Libert

doi:10.1007/s00018-013-1367-4

Abstract

Glucocorticoids (GCs) block inflammation via interference of the liganded glucocorticoid receptor (GR) with the activity of pro-inflammatory transcription factors NF-κB and AP-1, a mechanism known as transrepression. This mechanism is believed to involve the activity of GR monomers. Here, we explored how the GR monomer-favoring Compound A (CpdA) affects AP-1 activation and activity. Our results demonstrate that non-steroidal CpdA, unlike classic steroidal GCs, blocks NF-κB- but not AP-1-driven gene expression. CpdA rather sustains AP-1-driven gene expression, a result which could mechanistically be explained by the failure of CpdA to block upstream JNK kinase activation and concomitantly also phosphorylation of c-Jun. In concordance and in contrast to DEX, CpdA maintained the expression of the activated AP-1 target gene c-jun, as well as the production of the c-Jun protein. As for the underlying mechanism, GR is a necessary intermediate in the CpdA-mediated gene expression of AP-1-regulated genes, but seems to be superfluous to CpdA-mediated JNK phosphorylation prolongation. The latter phenomenon concurs with the inability of CpdA to stimulate DUSP1 gene expression. ChIP analysis demonstrates that DEX-activated GR, but not CpdA-activated GR, is recruited to AP-1-driven promoters. Furthermore, in mice we observed that CpdA instigates a strong enhancement of TNF-induced AP-1-driven gene expression. Finally, we demonstrate that this phenomenon coincides with an increased sensitivity towards TNF lethality, and implicate again a role for JNK2. In conclusion, our data support the hypothesis that a ligand-induced differential conformation of GR yields a different transcription factor cross-talk profile.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-013-1367-4) contains supplementary material, which is available to authorized users.

Highlights

The glucocorticoid receptor (GR, NR3C1) is a liganddependent transcription factor belonging to the subfamilyThe promoters of various genes coding for proteins involved in inflammatory processes, including cytokines, chemokines, and adhesion molecules harbor specific DNA sequences onto which the pro-inflammatory transcription factors NF-κB and/or AP-1 can bind
NF-κB has previously been described as a key transcription factor driving tumor necrosis factor (TNF)-induced IL-6 promoter activity [12]
This result suggests an inability of Compound A (CpdA)-activated GR to target the AP-1 element of the TNF-induced wild-type IL-6 promoter

Summary

Introduction

The glucocorticoid receptor (GR, NR3C1) is a liganddependent transcription factor belonging to the subfamilyThe promoters of various genes coding for proteins involved in inflammatory processes, including cytokines, chemokines, and adhesion molecules harbor specific DNA sequences onto which the pro-inflammatory transcription factors NF-κB and/or AP-1 can bind. Various stimuli, including cytokines (such as TNF-α) [10] and the microbial alkaloid staurosporine (STS) [11] result in the activation of nuclear NF-κB and/or AP-1, which contact their regulatory DNA sequences and, as such, drive gene transcription of, e.g., the cytokine Interleukin-6 (IL-6) [12]. This cytokine has been implicated in immune regulation and in endocrine and metabolic actions and aging. Understanding the regulation of this gene could contribute to a controlled and tissue-restricted modulation of its pleiotropic action profile

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Conclusion