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

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.

Glucocorticoids and the non-steroidal selective glucocorticoid receptor modulator, compound A, differentially affect colon cancer-derived myofibroblasts

“…Stimulation of this promoter with TNFa could be clearly counteracted by Dex and CpdA. In conclusion, despite the impaired ability of CpdA to translocate GR in CT5.3hTERT myofibroblasts, both compounds used are functional and show NFkB-transrepressive properties inL929sA cells, the latter of which corresponds with earlier reports in various cell types [12,13,16,17,20,[35][36][37]. The effects of Dex and CpdA on NFkB-mediated gene expression in CT5.3hTERT myofibroblasts is investigated more specifically in Fig.…”

“…5D and F). However, in contrast with previous research in adenocarcinomic human alveolar epithelial cells (A549) and in rheumatoid arthritis synovial fibroblasts (FLS) [37,42], CpdA is unexpectedly unable to significantly repress gene expression levels of MCP-1, IL1b and TNFa (Fig. 5B, C and E), indicating cell-specific mechanisms.…”

Effect of the Plant Derivative Compound A on the Production of Corticosteroid-Resistant Chemokines in Airway Smooth Muscle Cells

“…The observation that CpdA inhibits the expression of steroid-resistant chemokines at the mRNA level (Figure 2) strongly suggests that CpdA acted at the transcriptional level. Previous reports showed that CpdA repressed the function of different transcription factors, including NF-kB or AP-1 (defined as transrepression) (19,34,40,41), STAT6 (22), and T-bet (39). We now provide the first evidence that CpdA inhibits the activation of IRF-1 by affecting its nuclear accumulation ( Figure 6).…”

Modulatory effects of thymol and carvacrol on inflammatory transcription factors in lipopolysaccharide-treated macrophages

“…Salicylates and glucocorticoids are two commonly used anti-inflammatory drugs that have inhibitory effects on NF-jB activation (de Bosscher et al, 2014;Park et al, 2013). Other non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and flurbiprofen act similarly (D'Acquisto et al, 2002).…”