GR-independent down-modulation on GM-CSF bone marrow-derived dendritic cells by the selective glucocorticoid receptor modulator Compound A

ANDREONE, L; GIMENO, ML; ANTUNICA NOGUEROL, M; TUCKERMANN, JP; BARCALA TABARROZZI, AE; CASTRO, CN; BERGUER, PM; VETTORAZZI, S; PERONE, MJ; DECKERS, J; ARIOLFO, L; LIBERMAN, AC; DE BOSSCHER, K

Scientific Reports

Springer Nature

Año: 2016

Dendritic cells (DC) initiate the adaptive immune response. Glucocorticoids (GCs) down-modulate thefunction 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 CpdAon in vitro generated GM-CSF-conditioned bone marrow-derived DC (BMDC). CpdA-exposed BMDCexhibited low expression of cell-surface molecules and diminution of the release of proinflammatorycytokines upon LPS stimulation; processes associated with BMDC maturation and activation. CpdAtreatedBMDC were inefficient at Ag capture via mannose receptor-mediated endocytosis and displayedreduced T-cell priming. CpdA prevented the LPS-induced rise in pErk1/2 and pP38, kinases involved inTLR4 signaling. CpdA fully inhibited LPS-induced pAktSer473, a marker associated with the generationof tolerogenic DC. We used pharmacological blockade and selective genetic loss-of-function tools anddemonstrated GR-independent inhibitory effects of CpdA in BMDC. Mechanistically, CpdA-mediatedinactivation of the NF-κB intracellular signaling pathway was associated with a short-circuiting ofpErk1/2 and pP38 upstream signaling. Assessment of the in vivo function of CpdA-treated BMDC pulsedwith 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 benefitfor immune disorders, even when GR is not directly targeted.