Synergy between Vitamin D3 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.