FIG 4.

Vitamin D metabolism and cells of the immune system. Vitamin D₃ (VD₃) (cholecalciferol) is primarily acquired preformed in the diet or synthesized in the skin through the action of UVB radiation in sunlight from 7-dehydrocholesterol. VD₃ is metabolized first in the liver to 25-hydroxyvitamin D₃ [25(OH)VD₃] and then in the kidney to the most physiologically active metabolite, 1,25-dihydroxyvitamin D₃ [1,25(OH)₂VD₃]. VD₃ can also be metabolized by cells of the immune system (e.g., dendritic cells and macrophages) to 25(OH)VD₃ and 1,25(OH)₂VD₃ through the action of the enzymes CYP27A and CYP27B1, respectively. 1,25(OH)₂VD₃ acts on immune cells in an autocrine or paracrine manner through binding to the nuclear vitamin D receptor (VDR). Upon binding with 1,25(OH)₂VD₃, VDR heterodimerizes with nuclear receptors of the retinoic X receptor (RXR) family, and the complex binds to VD₃ response elements in the promoters of VD₃ response genes. CYP27B1 and VDR are upregulated in cells activated through TLR2, TLR4/NF-κB, and IFN-γ/STAT1. VD₃ has a largely suppressive effect on the adaptive immune system. Markers of dendritic cell maturation, activation, and antigen presentation are downregulated by exposure to 1,25(OH)₂VD₃. In particular, IL-12 production is diminished, leading to reduced Th1 differentiation, and suppressive cytokines such as IL-10 are upregulated. T lymphocytes show evidence of reduced proliferation, cytotoxic activity, and effector cytokine expression and increased regulatory function through increased regulatory T cell (Treg) and Th2 differentiation and IL-4 and IL-10 production. It is unclear if B cells express VDR or if their function is modulated indirectly through the reduced activity of antigen-presenting cells or reduced T cell help. B cells show reduced proliferation, differentiation to plasma cells, and immunoglobulin secretion. In contrast, monocytes and macrophages exposed to 1,25(OH)₂VD₃ have increased proinflammatory properties and produce antimicrobial peptides that are important for the innate immune response (211).