title: A dissociated glucocorticoid receptor modulator reduces airway hyperresponsiveness and inflammation in a mouse model of asthma.
abstract: The glucocorticoid receptor (GR) is a transcription factor able to support either target gene activation via direct binding to DNA or gene repression via interfering with the activity of various proinflammatory transcription factors. An improved therapeutic profile for combating chronic inflammatory diseases has been reported through selectively modulating the GR by only triggering its transrepression function. We have studied in this paper the activity of Compound A (CpdA), a dissociated GR modulator favoring GR monomer formation, in a predominantly Th2-driven asthma model. CpdA acted similarly to the glucocorticoid dexamethasone (DEX) in counteracting OVA-induced airway hyperresponsiveness, recruitment of eosinophils, dendritic cells, neutrophils, B and T cells, and macrophages in bronchoalveolar lavage fluid, lung Th2, Tc2, Th17, Tc17, and mast cell infiltration, collagen deposition, and goblet cell metaplasia. Both CpdA and DEX inhibited Th2 cytokine production in bronchoalveolar lavage as well as nuclear translocation of NF-κB and its subsequent recruitment onto the IκBα promoter in the lung. By contrast, DEX but not CpdA induces expression of the GR-dependent model gene MAPK phosphatase 1 in the lung, confirming the dissociative action of CpdA. Mechanistically, we demonstrate that CpdA inhibited IL-4-induced STAT6 translocation and that GR is essential for CpdA to mediate chemokine repression. In conclusion, we clearly show in this study the anti-inflammatory effect of CpdA in a Th2-driven asthma model in the absence of transactivation, suggesting a potential therapeutic benefit of this strategy.
authors.affiliation: Laboratoire d'Innovation Thérapeutique, Unité Mixte de Recherche 7200, Centre National de la Recherche Scientifique-Université de Strasbourg, Faculté de Pharmacie, F-67400 Illkirch, France.
authors.forename: Laurent L
authors.initials: LL
authors.lastname: Reber
authors.forename: François
authors.initials: F
authors.lastname: Daubeuf
authors.forename: Maud
authors.initials: M
authors.lastname: Plantinga
authors.forename: Lode
authors.initials: L
authors.lastname: De Cauwer
authors.forename: Sarah
authors.initials: S
authors.lastname: Gerlo
authors.forename: Wim
authors.initials: W
authors.lastname: Waelput
authors.forename: Serge
authors.initials: S
authors.lastname: Van Calenbergh
authors.forename: Jan
authors.initials: J
authors.lastname: Tavernier
authors.forename: Guy
authors.initials: G
authors.lastname: Haegeman
authors.forename: Bart N
authors.initials: BN
authors.lastname: Lambrecht
authors.forename: Nelly
authors.initials: N
authors.lastname: Frossard
authors.forename: Karolien
authors.initials: K
authors.lastname: De Bosscher
mesh_terms: D000085:Acetates; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000627:therapeutic use*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001249:Asthma / Q000188:drug therapy*; D016535:Bronchial Hyperreactivity / Q000188:drug therapy* / Q000503:physiopathology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D054638:Dual Specificity Phosphatase 1 / Q000096:biosynthesis / Q000235:genetics; D004790:Enzyme Induction / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D020397:Goblet Cells / Q000473:pathology; D007249:Inflammation; D007962:Leukocytes / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000473:pathology; D008407:Mast Cells / Q000276:immunology; D008679:Metaplasia; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000633:toxicity; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D011965:Receptors, Glucocorticoid / Q000187:drug effects* / Q000502:physiology; D050800:STAT6 Transcription Factor / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D014439:Tyramine / Q000031:analogs & derivatives
chemical_list: C104564:2-(4-acetoxyphenyl)-2-chloro-N-methylethylamine; D000085:Acetates; D018927:Anti-Asthmatic Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D000644:Quaternary Ammonium Compounds; D011965:Receptors, Glucocorticoid; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D003907:Dexamethasone; D010047:Ovalbumin; D054638:Dual Specificity Phosphatase 1; D014439:Tyramine