Immunoregulation by 1,25-dihydroxyvitamin D3: Basic concepts

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3), the biologically active metabolite of Vitamin D3, not only regulates bone and calcium metabolism but also exerts other biological activities, including immunomodulation via the nuclear Vitamin D receptor expressed in antigen-presenting cells and activated T cells. This regulation is mediated through interference with nuclear transcription factors such as NF-AT and NF-κB or by direct interaction with Vitamin D responsive elements in the promoter regions of cytokine genes. Dendritic cells (DCs) are primary targets for the immunomodulatory activity of 1,25(OH)2D3, as indicated by inhibited DC differentiation and maturation, leading to down-regulated expression of MHC-II, costimulatory molecules and IL-12. Moreover, 1,25(OH)2D3 enhances IL-10 production and promotes DC apoptosis. Together, these effects of 1,25(OH)2D3 inhibit DC-dependent T cell activation. Immunomodulation by 1,25(OH)2D3 and its analogs in vivo has been demonstrated in different models of autoimmune diseases and transplantation. Moreover, combining analogs with other immunosuppressants leads to synergism in models of autoimmunity and transplantation. The availability of 1,25(OH)2D3 analogs with immunomodulatory activity at non-hypercalcemic doses may allow exploitation of their immunomodulatory effects in a clinical setting of treatment of autoimmune diseases and prevention of allograft rejection.