Synergy between Vitamin D(3) and Toll-Like Receptor Agonists Regulates Human Dendritic Cell Response during Maturation

Human dendritic cells (DC) can be differentiated from blood monocytes in the presence of GM-CSF and IL-4 and matured by lipopolysaccharide (LPS). Vitamin D(3) inhibits the maturation of human DC measured by changes in surface expression of HLA-DR, CD14, CD40, CD80, CD83, and CD86. We here examine the function of vitamin D(3) during DC maturation. One of the earliest changes to LPS-induced maturation was an increase in CD83 expression. Vitamin D(3) inhibited the increase in expression of HLA-DR, CD40, CD80, CD83, and CD86 and the decrease in expression of CD14, which was paralleled morphologically by vitamin D(3)-induced inhibition of dendritic cell differentiation. Vitamin D(3) acted in synergy with the TLR agonists LPS and peptidoglycan (PGN) in inducing IL-6, IL-8, and IL-10, whereas vitamin D(3) completely inhibited LPS-induced secretion of IL-12. The synergy occurred at concentrations where neither vitamin D(3) nor the TLR agonists alone induced measurable cytokine secretion. Both LPS and PGN enhanced the level of the vitamin D(3) receptor (VDR). Taken together, these data demonstrated that vitamin D(3) and TLR agonists acted in synergy to alter secretion of cytokines from human DC in a direction that may provide an anti-inflammatory environment.