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.

Galectin-8 activates dendritic cells and stimulates antigen-specific immune response elicitation

“…Percentages for each subset (29.2 vs. 61.6, respectively) were in agreement with previous reports [23,24]. Incubation with 2 mM Gal-8 for 18 h induced the expression of CD86 in both CD11c + BMDC subsets, whereas expression of CD80 was induced only in MHCII high /CD11b int cells (Fig.…”

“…With the possibility that Gal-8 may stimulate APC to sustain T cell activation after priming, we investigated whether this lectin displayed a direct effect on DC function. BMDCs, differentiated in vitro from GM-CSF/IL-4 conditioned mice bone marrow cultures, constitute a DC model that has been largely used to study many aspects of APCs [19][20][21][22][23]. Recently, it has been demonstrated that CD11c + BMDC cultures comprise a heterogeneous population of DCs (GM-DC) and macrophages (GM-M) [24].…”

Protective Effect of Eckol against Acute Hepatic Injury Induced by Carbon Tetrachloride in Mice

“…In order to understand whether the protective effect of eckol against acute hepatic injury was related to dendritic cells, we performed the immunohistochemical staining for CD11c, a commonly used and classical dendritic cell-specific marker [ 34 ]. As shown in Figure 5 , in the eckol-treated groups, more liver cells expressing CD11c were identified to infiltrate into the portal area and parenchyma of the liver, suggesting the dendritic cell recruitment activity of eckol might be responsible for the enhanced production of anti-inflammatory IL-10 in liver tissues, and therefore, might be a part of mechanisms underlying the protective effect of eckol against acute hepatic injury induced by CCl 4 .…”

Interactions Between the Neuroendocrine System and T Lymphocytes in Diabetes

“…Glucocorticoids affect gene expression by two main GR-dependent and -independent intracellular mechanisms that exert several biological effects. These differential mechanisms have fueled the interest in the study and development of new GR-ligands with dissociative properties combining GCs’ anti-inflammatory properties with a reduced side effect profile ( 175 , 176 ). These particular dissociated GR-ligands hold potential for their use in Th1-mediated immune disorders.…”