Glucocorticoid-mediated regulation of thymic dendritic cell function

Abstract

The possible effects of glucocorticoids (GC) on the biology of thymic dendritic cells (DC) have been analyzed. Both DC and GC seem to be involved in intrathymic T cell selection but possible relationships, if any, between them remain currently unknown. For the first time, we have proved the expression of GC receptors in thymic DC. Moreover, our data demonstrate that in vitro dexamethasone (Dex) treatment barely affects the viability of mature thymic DC, which are largely resistant to its apoptotic effect. Dex-treated thymic DC also show a slightly reduced surface expression of some adhesion and co-stimulatory molecules in correlation with diminished allostimulatory properties. Furthermore, the production of both IL-1beta and tumor necrosis factor (TNF)-alpha, but not that of IL-6 and IL-10, diminished in the mixed leukocyte reaction established with Dex-treated thymic DC. However, the addition of recombinant rat IL-1beta and TNF-alpha, alone or in combination, did not recover the allostimulatory capacity. Taken together, these results support certain GC-mediated regulation of the activity of thymic DC which could be relevant for the biology of the thymus gland.

Glucocorticoid receptor translational isoforms underlie maturational stage-specific glucocorticoid sensitivities of dendritic cells in mice and humans

“…Although previous studies have examined GR expression in DCs, 9,10,22,25 none of these studies have evaluated the GR translational isoforms. To determine the mechanisms underlying the maturational stage-specific glucocorticoid sensitivity of DCs, we examined the GR isoforms expressed in BMDCs at various stages of maturation using Western blot analysis.…”

“…7,8 Addition of glucocorticoids during DC activation results in reduced expression of surface MHC II and costimulatory molecules, suppressed proinflammatory cytokines, and increased interleukin (IL)-10 production. [8][9][10][11][12][13][14] Antigen processing and presentation by DCs are almost completely inhibited when antigen pulsing is performed in the presence of glucocorticoids. 11,12,15 Consequently, glucocorticoids impair T-cell stimulatory capacity of DCs.…”

“…11,12,15 Consequently, glucocorticoids impair T-cell stimulatory capacity of DCs. 13,14,16,17 In addition, glucocorticoids may reduce the number of DCs via inhibiting DC migration and increasing DC apoptosis, 7,9,10,12,15,[18][19][20][21][22][23][24][25] although some other reports suggest that glucocorticoids do not induce DCs apoptosis. 13,16,26,27 It is not known whether different DC subsets have differential sensitivity to glucocorticoid-induced apoptosis.…”

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

“…Glucocorticoids have been shown to inhibit maturation of murine DCs (24) by reducing the expression of adhesion molecules and co-stimulatory molecules, resulting in diminished priming and activation of specific T cells (25,26) or up-regulation of IL-10 secreting T regulatory cells (27). Cultured adult human cells that are treated with glucocorticoids decrease expression of DC co-stimulatory molecules (29,32), retard DC differentiation and maturation (29 -32), alter DC endocytic function, and weaken DC immunostimulatory capacity in antigen presentation to autologous T cells (29,30,33,35,36).…”

“…DCs that express this immature phenotype have diminished ability to prime Th cells and to enhance the formation of T regulatory cells (25)(26)(27). Studies using human DCs derived from adult peripheral blood (AB) indicate that glucocorticoids 1) retard DC differentiation and maturation (28,29) in a doseand length-of-exposure-dependent manner (30 -32); 2) decrease expression of co-stimulatory molecules (29,32); 3) alter DC functioning by increasing endocytosis, increasing secretion of IL-10 (28,29,33,34) while decreasing IL-12 (29); and 4) weaken the immunostimulatory capacity of DCs in antigen presentation to autologous T cells in mixed lymphocyte reactions (29,30,35,36).…”