Artículos de revistas
GR-independent down-modulation on GM-CSF bone marrow-derived dendritic cells by the selective glucocorticoid receptor modulator Compound A
Fecha
2016-11Registro en:
Barcala Tabarrozzi, Andrés Ezequiel; Andreone, Luz; Deckers, Julie; Castro, Carla Noemí; Gimeno, Maria Laura; et al.; GR-independent down-modulation on GM-CSF bone marrow-derived dendritic cells by the selective glucocorticoid receptor modulator Compound A; Springer Nature; Scientific Reports; 6; 11-2016; 1-16
2045-2322
2045-2322
CONICET Digital
CONICET
Autor
Barcala Tabarrozzi, Andrés Ezequiel
Andreone, Luz
Deckers, Julie
Castro, Carla Noemí
Gimeno, Maria Laura
Ariolfo, Laura
Berguer, Paula Mercedes
Antunica Noguerol, María de Las Nieves
Liberman, Ana Clara
Vettorazzi, Sabine
Tuckermann, Jan P.
De Bosscher, Karolien
Perone, Marcelo Javier
Resumen
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.