Distinctive dendritic cell modulation by vitamin D₃ and glucocorticoid pathways

Dendritic cell (DC) maturation plays a central role in regulating immunity. We show that glucocorticoid and 1α,25(OH)₂D₃ agonists modulate DCs via distinct and additive signaling pathways. Phenotypic and functional indices were examined in DCs treated with dexamethasone (DEX) and/or a 1α,25(OH)₂D₃ analog (D₃ analog). DEX potently attenuated pro-inflammatory cytokines and chemokines but had modest, reversible effects on T-cell stimulatory capacity. D₃ analog produced significantly greater inhibition of T-cell stimulation in vitro and in vivo and, unlike DEX, increased expression of the chemokines MCP-1 and MIP-1α. Both DEX and D₃ analog were associated with reduced expression of the NF-κB proteins c-Rel and Rel B but not Rel A. Combined DEX and D₃ analog treatment of DCs resulted in significant additive inhibition of pro-inflammatory cytokines, T-cell stimulation, chemokines, chemokine receptors, and NF-κB components. Additive inhibition was most striking for RANTES, CCR5, CCR7, and Rel B. The combined effects of the two hormonal pathways on DCs have unique immunomodulatory potential.