Regulation of CYP27B1 and CYP24A1 hydroxylases limits cell‐autonomous activation of vitamin D in dendritic cells

Abstract

The active vitamin D metabolite 1α,25‐dihydroxyvitamin D (1,25[OH]₂D) potently inhibits DC priming of T‐cell activation, suggesting that it mediates a homeostatic role in this context. Therefore, careful regulation of 1,25[OH]₂D levels is necessary to avoid inappropriate inhibition of T‐cell activation. Cell‐autonomous control of vitamin D activity can be modulated by the action of the vitamin D‐activating and ‐inactivating hydroxylases, CYP27B1, and CYP24A1, respectively. We show that in comparison to macrophages, human monocyte‐derived DCs exhibit significantly less activation of 25‐dihydroxyvitamin D to 1,25[OH]₂D, and that DCs predominantly express a truncated CYP27B1 transcript that may contribute to the deficiency in activation of vitamin D. Furthermore, in response to stimulation with 1,25[OH]₂D, upregulation of the inactivating enzyme CYP24A1 curtailed the functional effects of vitamin D in DCs, but not macrophages. Production of 1,25[OH]₂D by macrophages was adequate to induce expression of vitamin D‐responsive genes by DCs, inhibit DC maturation in response to innate immune stimulation and DC‐dependent T‐cell responses. Our data suggest that in comparison to macrophages, differential regulation of hydroxylases limits autocrine vitamin D activity in DCs, and that paracrine activation of vitamin D exerts a more potent mechanism for homeostatic control of DC function.