Kwok-Ho Yip1, Natasha Kolesnikoff1, Chunping Yu2, Nicholas Hauschild1, Houng Taing2, Lisa Biggs1, David Goltzman3, Philip A Gregory1, Paul H Anderson4, Michael S Samuel5, Stephen J Galli6, Angel F Lopez5, Michele A Grimbaldeston7. 1. Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia. 2. Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia; University of Adelaide, Adelaide, Australia. 3. Departments of Medicine and Physiology, McGill University, Montreal, Quebec, Canada. 4. University of South Australia, Adelaide, Australia. 5. Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia; University of Adelaide, Adelaide, Australia; University of South Australia, Adelaide, Australia. 6. Departments of Pathology and of Microbiology and Immunology, Stanford University School of Medicine, Stanford, Calif. 7. Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia; University of Adelaide, Adelaide, Australia; University of South Australia, Adelaide, Australia. Electronic address: michele.grimbaldeston@health.sa.gov.au.
Abstract
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 1α,25-dihydroxyvitamin D3 (1α,25[OH]2D3) or its predominant inactive precursor metabolite in the circulation, 25-hydroxyvitamin D3 (25OHD3), can influence IgE-mediated mast cell activation and passive cutaneous anaphylaxis (PCA) in vivo. OBJECTIVE: We sought to assess whether the vitamin D3 metabolites 25OHD3 and 1α,25(OH)2D3 can repress IgE-dependent mast cell activation through mast cell-25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) and mast cell-VDR activity. METHODS: We measured the extent of vitamin D3 suppression of IgE-mediated mast cell degranulation and mediator production in vitro, as well as the vitamin D3-induced curtailment of PCA responses in WBB6F1-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 25OHD3 to 1α,25(OH)2D3 through CYP27B1 activity and that both of these vitamin D3 metabolites suppressed IgE-induced mast cell-derived proinflammatory and vasodilatory mediator production in a VDR-dependent manner in vitro. Furthermore, epicutaneously applied vitamin D3 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 D3 on mast cell function by demonstrating that mast cells can actively metabolize 25OHD3 to dampen IgE-mediated mast cell activation in vitro and in vivo.
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 1α,25-dihydroxyvitamin D3 (1α,25[OH]2D3) or its predominant inactive precursor metabolite in the circulation, 25-hydroxyvitamin D3 (25OHD3), can influence IgE-mediated mast cell activation and passive cutaneous anaphylaxis (PCA) in vivo. OBJECTIVE: We sought to assess whether the vitamin D3 metabolites 25OHD3 and 1α,25(OH)2D3 can repress IgE-dependent mast cell activation through mast cell-25-hydroxyvitamin D-1α-hydroxylase (CYP27B1) and mast cell-VDR activity. METHODS: We measured the extent of vitamin D3 suppression of IgE-mediated mast cell degranulation and mediator production in vitro, as well as the vitamin D3-induced curtailment of PCA responses in WBB6F1-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 25OHD3 to 1α,25(OH)2D3 through CYP27B1 activity and that both of these vitamin D3 metabolites suppressed IgE-induced mast cell-derived proinflammatory and vasodilatory mediator production in a VDR-dependent manner in vitro. Furthermore, epicutaneously applied vitamin D3 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 D3 on mast cell function by demonstrating that mast cells can actively metabolize 25OHD3 to dampen IgE-mediated mast cell activation in vitro and in vivo.
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