Regulation of 25-hydroxyvitamin D3-1α-hydroxylase and production of 1α,25-dihydroxyvitamin D3 by human dendritic cells

Abstract

25-Hydroxyvitamin D₃-1α-hydroxylase (25(OH)D₃-1α-hydroxylase), the key enzyme of 1α,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) production, is expressed in monocyte-derived macrophages (MACs). Here we show for the first time constitutive expression of 25(OH)D₃-1α-hydroxylase in monocyte-derived dendritic cells (DCs), which was increased after stimulation with lipopolysaccharide (LPS). Accordingly, DCs showed low constitutive production of 1,25(OH)₂D₃, but activation by LPS increased 1,25(OH)₂D₃ synthesis. In addition, 25(OH)D₃-1α-hydroxylase expression was found in blood DCs but not in CD34⁺-derived DCs. Next we analyzed the functional consequences of these results. Addition of 1,25(OH)₂D₃ at concentrations comparable with those produced by DCs inhibited the allostimulatory potential of DCs during the early phase of DC differentiation. However, terminal differentiation decreased the responsiveness of DCs to 1,25(OH)₂D₃. In conclusion, DCs are able to produce 1,25(OH)₂D₃ especially following stimulation with LPS. Terminal maturation renders DCs unresponsive to the effects of 1,25(OH)₂D₃, but those cells are able to suppress the differentiation of their own precursor cells in a paracrine way through the production of 1,25(OH)₂D₃.