VDR-dependent regulation of mast cell maturation mediated by 1,25-dihydroxyvitamin D3

1,25-Dihydroxyvitamin D-3 [1,25(OH)(2)D-3] is a secosteroid hormone that regulates bone metabolism, controls calcium homeostasis, and possesses immunomodulatory properties. We show here that 1,25(OH)(2)D-3 contributes to the regulation of development and function of mast cells, which play a critical role in several inflammatory disorders. 1,25(OH)(2)D-3 promotes apoptosis and inhibits maturation of mouse bone marrow-derived mast cell precursors. Dose-dependent inhibition of mast cell differentiation by 1,25(OH)2D3 is observed at discrete, intermediate stages of mast cell development, identified by expression of c-kit, Fc epsilon RI, and IL-3 receptor-et chain, and depends on the expression of the vitamin D receptor (VDR). It is important that mast cell progenitors obtained from VDR-ablated mice undergo an accelerated maturation in vitro and give rise to more responsive mast cells than wild-type. Furthermore, histological analysis of mast cell density in peripheral tissues reveals a moderate increase in the number of mast cells in the skin of VDR-deficient mice compared with wild-type animals. These data support the hypothesis of a physiological role of 1,25(OH)2D3 in mast cell development and suggest novel, therapeutic uses of 1,25(OH)2D3 analogs.