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J Allergy Clin Immunol. 2014 May;133(5):1356-64, 1364.e1-14. doi: 10.1016/j.jaci.2013.11.030. Epub 2014 Jan 22.

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

Author information

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.

KEYWORDS:

CYP27B1; IgE; Mast cells; anaphylaxis; inflammation; vitamin D receptor; vitamin D(3)

PMID:
24461581
PMCID:
PMC4154631
DOI:
10.1016/j.jaci.2013.11.030
[Indexed for MEDLINE]
Free PMC Article

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