title: 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.
authors.affiliation: Laboratory of Eukaryotic Gene Expression & Signal Transduction (LEGEST), Department of Physiology, Ghent University, Ghent, Belgium, karolien.debosscher@vib-ugent.be.
authors.forename: Karolien
authors.initials: K
authors.lastname: De Bosscher
authors.forename: Ilse M
authors.initials: IM
authors.lastname: Beck
authors.forename: Lien
authors.initials: L
authors.lastname: Dejager
authors.forename: Nadia
authors.initials: N
authors.lastname: Bougarne
authors.forename: Anthoula
authors.initials: A
authors.lastname: Gaigneaux
authors.forename: Sébastien
authors.initials: S
authors.lastname: Chateauvieux
authors.forename: Dariusz
authors.initials: D
authors.lastname: Ratman
authors.forename: Marc
authors.initials: M
authors.lastname: Bracke
authors.forename: Jan
authors.initials: J
authors.lastname: Tavernier
authors.forename: Wim
authors.initials: W
authors.lastname: Vanden Berghe
authors.forename: Claude
authors.initials: C
authors.lastname: Libert
authors.forename: Marc
authors.initials: M
authors.lastname: Diederich
authors.forename: Guy
authors.initials: G
authors.lastname: Haegeman
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003907:Dexamethasone / Q000494:pharmacology; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048056:Mitogen-Activated Protein Kinase 9 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D015850:Interleukin-6; D016328:NF-kappa B; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid; D018808:Transcription Factor AP-1; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; C524574:compound A (octyltriazole); D003907:Dexamethasone; D048056:Mitogen-Activated Protein Kinase 9; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D019311:Staurosporine