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

BARACALA TABARROZZI A; CASTRO C; BERGUER P; VETTORAZZI S; PERONE M; ANDREONE L; GIMENO M; ANTUNICA NOGUEROL M; TUCKERMANN J; DECKERS J; ARIOLFO L; LIBERMAN A; DE BOSSCHER K

Scientific Reports

Springer Nature

Lugar: Londres; Año: 2016

Glucocorticoids (GCs) influence several biological processes and play an important role in the immune response. Dendritic cells (DC) initiate and tune both the innate and adaptive immune responses, and are targets of GCs. Synthetic corticoids, like dexamethasone, down-modulate the function of DC. Compound A (CpdA, (2-(4-acetoxyphenyl)-2-chloro-N-methyl-ethylammonium chloride) is a plant-derived compound which has been reported as a GR-ligand with marked dissociative properties. In this study we investigated the immunomodulatory effects of CpdA on LPS-activated bone marrow-derived DC. CpdA-exposed DC exhibited low expression of cell-surface molecules and diminution of the release of proinflammatory cytokines IL12p70, TNF and IL6 upon LPS stimulation; processes associated with DC maturation and activation. CD11c expression was unaffected. CpdA-treated DC were inefficient at Ag capture via mannose receptor-mediated endocytosis. Accordingly, CpdA-treated DC displayed a decreased T-cell allo- and syngeneic-stimulatory potential. CpdA prevented the LPS-induced rise in pErk1/2 and pP38, kinases involved in TLR4 signaling, to a similar extent as Dex did in DC. CpdA fully inhibited LPS-induced pAktSer473 that has been associated with the generation of tolerogenic DC. Dex inhibited LPS-induced pAkt in DC to a much lower extent than CpdA. We found that the inhibitory effects of CpdA in DC might be explained by a GR-independent (nongenomic) inactivation of the NF-B intracellular signaling pathway associated with pErk1/2 and pP38 upstream signaling. Assessment of the in vivo function of CpdA-treated DC pulsed with the hapten trinitrobenzenesulfonic acid showed impaired cell-mediated contact hypersensitivity. Collectively, we provide evidence that CpdA is an effective DC modulator and propose that it?s worthwile to investigate the potential of dissociative GR modulators to modulate DC maturation and activation.