title: GR-independent down-modulation on GM-CSF bone marrow-derived dendritic cells by the selective glucocorticoid receptor modulator Compound A.
abstract: Dendritic cells (DC) initiate the adaptive immune response. Glucocorticoids (GCs) down-modulate the function of DC. Compound A (CpdA, (2-(4-acetoxyphenyl)-2-chloro-N-methyl-ethylammonium chloride) is a plant-derived GR-ligand with marked dissociative properties. We investigated the effects of CpdA on in vitro generated GM-CSF-conditioned bone marrow-derived DC (BMDC). CpdA-exposed BMDC exhibited low expression of cell-surface molecules and diminution of the release of proinflammatory cytokines upon LPS stimulation; processes associated with BMDC maturation and activation. CpdA-treated BMDC were inefficient at Ag capture via mannose receptor-mediated endocytosis and displayed reduced T-cell priming. CpdA prevented the LPS-induced rise in pErk1/2 and pP38, kinases involved in TLR4 signaling. CpdA fully inhibited LPS-induced pAktSer473, a marker associated with the generation of tolerogenic DC. We used pharmacological blockade and selective genetic loss-of-function tools and demonstrated GR-independent inhibitory effects of CpdA in BMDC. Mechanistically, CpdA-mediated inactivation of the NF-κB intracellular signaling pathway was associated with a short-circuiting of pErk1/2 and pP38 upstream signaling. Assessment of the in vivo function of CpdA-treated BMDC pulsed with the hapten trinitrobenzenesulfonic acid showed impaired cell-mediated contact hypersensitivity. Collectively, we provide evidence that CpdA is an effective BMDC modulator that might have a benefit for immune disorders, even when GR is not directly targeted.
authors.affiliation: Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires, Argentina.
authors.forename: Andres E
authors.initials: AE
authors.lastname: Barcala Tabarrozzi
authors.affiliation: Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires, Argentina.
authors.forename: Luz
authors.initials: L
authors.lastname: Andreone
authors.affiliation: Receptor Research Laboratories, Nuclear Receptor Lab, VIB-Department of Medical Protein Research, VIB, Ghent University, Gent, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Deckers
authors.affiliation: Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires, Argentina.
authors.forename: Carla N
authors.initials: CN
authors.lastname: Castro
authors.affiliation: Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires, Argentina.
authors.forename: María L
authors.initials: ML
authors.lastname: Gimeno
authors.affiliation: Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires, Argentina.
authors.forename: Laura
authors.initials: L
authors.lastname: Ariolfo
authors.affiliation: Fundación Instituto Leloir, IIBBA, CONICET, Buenos Aires, Argentina.
authors.forename: Paula M
authors.initials: PM
authors.lastname: Berguer
authors.affiliation: Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires, Argentina.
authors.forename: María
authors.initials: M
authors.lastname: Antunica-Noguerol
authors.affiliation: Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires, Argentina.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Liberman
authors.affiliation: Institute for Comparative Molecular Endocrinology, University of Ulm, Ulm, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Vettorazzi
authors.affiliation: Institute for Comparative Molecular Endocrinology, University of Ulm, Ulm, Germany.
authors.forename: Jan P
authors.initials: JP
authors.lastname: Tuckermann
authors.affiliation: Receptor Research Laboratories, Nuclear Receptor Lab, VIB-Department of Medical Protein Research, VIB, Ghent University, Gent, Belgium.
authors.forename: Karolien
authors.initials: K
authors.lastname: De Bosscher
authors.affiliation: Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA) - CONICET - Partner Institute of the Max Planck Society, Buenos Aires, Argentina.
authors.forename: Marcelo J
authors.initials: MJ
authors.lastname: Perone
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D018122:B7-1 Antigen / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects*; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects*; D015536:Down-Regulation; D004705:Endocytosis / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000502:physiology*; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D011965:Receptors, Glucocorticoid / Q000187:drug effects* / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000187:drug effects / Q000378:metabolism; D014439:Tyramine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C104564:2-(4-acetoxyphenyl)-2-chloro-N-methylethylamine; D000085:Acetates; D018122:B7-1 Antigen; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D011965:Receptors, Glucocorticoid; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D014439:Tyramine