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 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.


CONCLUSIONS
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.
Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia.
Kwok-Ho
KH
Yip
Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia.
Natasha
N
Kolesnikoff
Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia; University of Adelaide, Adelaide, Australia.
Chunping
C
Yu
Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia.
Nicholas
N
Hauschild
Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia; University of Adelaide, Adelaide, Australia.
Houng
H
Taing
Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia.
Lisa
L
Biggs
Departments of Medicine and Physiology, McGill University, Montreal, Quebec, Canada.
David
D
Goltzman
Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia.
Philip A
PA
Gregory
University of South Australia, Adelaide, Australia.
Paul H
PH
Anderson
Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia; University of Adelaide, Adelaide, Australia; University of South Australia, Adelaide, Australia.
Michael S
MS
Samuel
Departments of Pathology and of Microbiology and Immunology, Stanford University School of Medicine, Stanford, Calif.
Stephen J
SJ
Galli
Division of Human Immunology, Centre for Cancer Biology, SA Pathology, Adelaide, Australia; University of Adelaide, Adelaide, Australia; University of South Australia, Adelaide, Australia.
Angel F
AF
Lopez
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.
Michele A
MA
Grimbaldeston
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism*; D000707:Anaphylaxis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002112:Calcifediol / Q000378:metabolism*; D002460:Cell Line; D003876:Dermatitis, Atopic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007073:Immunoglobulin E; D008407:Mast Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*
D018167:Receptors, Calcitriol; D007073:Immunoglobulin E; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002112:Calcifediol
CYP27B1; IgE; Mast cells; anaphylaxis; inflammation; vitamin D receptor; vitamin D(3)