Opposing effects of dehydroepiandrosterone and dexamethasone on the generation of monocyte-derived dendritic cells

Abstract

Background: Dehydroepiandrosterone (DHEA) has been suggested as an immunostimulating steroid hormone, of which the effects on the development of dendritic cells (DC) are unknown. The effects of DHEA often oppose those of the other adrenal glucocorticoid, cortisol. Glucocorticoids (GC) are known to suppress the immune response at different levels and have recently been shown to modulate the development of DC, thereby influencing the initiation of the immune response. Variations in the duration of exposure to, and doses of, GC (particularly dexamethasone (DEX)) however, have resulted in conflicting effects on DC development. Aim: In this study, we describe the effects of a continuous high level of exposure to the adrenal steroid DHEA (10 26 M) on the generation of immature DC from monocytes, as well as the effects of the opposing steroid DEX on this development. Results: The continuous presence of DHEA (10 26 M) in GM-CSF/IL-4-induced monocyte-derived DC cultures resulted in immature DC with a morphology and functional capabilities similar to those of typical immature DC (T cell stimulation, IL-12/IL-10 production), but with a slightly altered phenotype of increased CD80 and decreased CD43 expression (markers of maturity).The continuous presence of DEX at a concentration of 10 26 M in the monocyte/DC cultures resulted in the generation of plastic-adherent macrophage-like cells in place of typical immature DC, with increased CD14 expression, but decreased expression of the typical DC markers CD1a, CD40 and CD80. These cells were strongly reactive to acid phosphatase, but equally capable of stimulating T cell proliferation as immature DC. The production of IL-12 by these macrophage-like cells was virtually shut down, whereas the production of IL-10 was significantly higher than that of control immature DC. Conclusion:The continuous presence of a high level of GC during the generation of immature DC from monocytes can modulate this development away from DC towards a macrophage-like cell. The combination of a low CD80 expression and a shutdown of IL-12 production suggests the possibility of DEX-generated cells initiating a Th2-biased response. These effects by DEX on DC development contrast with those by DHEA, which resulted in a more typical DC although possessing a phenotype possibly indicating a more mature state of the cell.

Dexamethasone Inhibits Maturation and Alters Function of Monocyte-Derived Dendritic Cells from Cord Blood

“…DEXAMETHASONE AND NEONATAL DENDRITIC CELLS a counterbalancing Th1 cytokine, confirms the work of others (29,33,34,44). The observation that Dx added to CB cells during the differentiation stage dramatically amplified the modulation compared with AB cells extends previous observations (Fig.…”

“…The results suggest that Dx is instrumental in sustaining macrophage-like cells in CB cultures, and these data are consistent with the hypothesis that Dx is a genomic-affecting steroid (43). Canning et al (44) reported a similar increase of CD14 expression when Dx was added during the differentiation stage in a human adult monocyte/DC culture, although Dx effect during the maturation stage was not studied.…”

CYP7B expression and activity in fibroblast‐like synoviocytes from patients with rheumatoid arthritis: Regulation by proinflammatory cytokines

“…Currently, RA can be successfully treated with glucocorticoids (1). It has been suggested that the immunosuppressive effects of glucocorticoids may be counteracted by the naturally occurring dehydroepiandrosterone (DHEA) (2,3). More recent data, however, suggest that 7␣-hydroxy-DHEA (7␣-OH-DHEA), rather than DHEA itself, prevents the immunosuppressive effects of glucocorticoids (4).…”

Hormones and immune function: implications of aging

“…In rodents, DHEA antagonizes dexamethasone-induced suppression of lymphocyte proliferation and prevents glucocorticoid-induced thymic and splenic atrophy (Blauer et al ., 1991). DHEA and dexamethasone may have opposing effects on dendritic cell differentiation (Canning et al ., 2000). DHEA and the glucocorticoid receptor antagonist RU486 equally reverse the suppressive effects of glucocorticoids on immune function (Araneo & Daynes, 1995).…”