Mechanisms of vitamin D3 metabolite repression of IgE-dependent mast cell activation

Background: Mast cells have gained notoriety based on their detrimental contributions to IgE-mediated allergic disorders. Although mast cells express the vitamin D receptor (VDR), it is not clear to what extent 1 alpha, 25-dihydroxyvitamin D-3 (1 alpha, 25[OH](2)D-3) or its predominant inactive precursor metabolite in the circulation, 25-hydroxyvitamin D-3 (25OHD(3)), can influence IgE-mediated mast cell activation and passive cutaneous anaphylaxis (PCA) in vivo. Objective: We sought to assess whether the vitaminD(3) metabolites 25OHD(3) and 1 alpha, 25(OH)(2)D-3 can repress IgE-dependent mast cell activation through mast cell-25-hydroxyvitamin D-1 alpha-hydroxylase (CYP27B1) and mast cell-VDR activity. Methods: We measured the extent of vitamin D-3 suppression of IgE-mediated mast cell degranulation and mediator production in vitro, as well as the vitamin D-3-induced curtailment of PCA responses in WBB6F(1)-Kit(W/W-v) or C57BL/6J-Kit(W-sh/W-sh) mice engrafted with mast cells that did or did not express VDR or CYP27B1. Results: Here we show that mouse and human mast cells can convert 25OHD(3) to 1 alpha, 25(OH)(2)D-3 through CYP27B1 activity and that both of these vitaminD(3) metabolites suppressed IgE-induced mast cell-derived proinflammatory and vasodilatory mediator production in a VDR-dependent manner in vitro. Furthermore, epicutaneously applied vitamin D-3 metabolites significantly reduced the magnitude of skin swelling associated with IgE-mediated PCA reactions in vivo; a response that required functional mast cell-VDRs and mast cell-CYP27B1. Conclusion: Taken together, our findings provide a mechanistic explanation for the anti-inflammatory effects of vitamin D-3 on mast cell function by demonstrating that mast cells can actively metabolize 25OHD(3) to dampen IgE-mediated mast cell activation in vitro and in vivo.