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https://hdl.handle.net/2440/91205
Type: | Thesis |
Title: | Immunoregulatory effects of vitamin D3 on mast cells during immunoglobulin E-dependent immune responses. |
Author: | Yu, Chunping |
Issue Date: | 2014 |
School/Discipline: | School of Molecular and Biomedical Science |
Abstract: | Mast cells (MCs) can exert anti-inflammatory effects via production of interleukin (IL)- 10 in a number of Immunoglobulin (Ig)E-independent immune responses. Recently, we reported that 1α,25-dihydroxyvitamin D₃ (1α,25(OH)₂D₃), the biologically active form of vitamin D₃ (VitD₃), can induce IL-10 production from mouse bone marrow-derived cultured MCs (mBMCMCs). For the current project, we further investigated if the well-recognised pro-inflammatory properties of MCs in IgE-dependent immune settings can be reduced upon 1α,25(OH)₂D₃ administration and, if so, which mechanisms are likely to be responsible. In the presence of 1α,25(OH)₂D₃, IgE + specific antigen (sAg)-stimulated mBMCMCs exhibited reduced degranulation, as well as decreased production of the pro-inflammatory cytokines, TNFα and IL-6, in a vitamin D receptor (VDR)-dependent manner. Concomitantly, 1α,25(OH)₂D₃ significantly up-regulated the production of IL-10. In addition, we demonstrated for the first time the expression of CYP27B1, the enzyme that generates 1α,25(OH)₂D₃ from its inactive precursor 25-hydroxyvitamin D3 (25OHD₃ ) in both mBMCMCs and human cord-blood-derived MCs (hCBMCs). This enables mBMCMCs to produce endogenous 1α,25(OH)₂D₃ and thus granting 25OHD₃ similar VDR-dependent immunosuppressive effects to 1α,25(OH)₂D₃ on activated MCs either directly or indirectly. By employing a mouse IgE-mediated MC-dependent passive cutaneous anaphylaxis (PCA) model as well as four mouse groups with different cutaneous MC profiles in the ears, including wild-type (WT) C57BL/6 mice, MC-deficient C57BL/6-Kitʷ⁻ˢʰʹʷ⁻ˢʰ mice and C57BL/6-Kitʷ⁻ˢʰʹʷ⁻ˢʰ mice engrafted with either WT or VDR-deficient (VDR⁻ʹ⁻) mBMCMCs, we found that topical application of either 1α,25(OH)₂D₃ or 25OHD₃ significantly curtailed the magnitude of PCA-associated ear swelling, potentially by reducing the extent of MC degranulation and/or the secretion of various MC-derived cytokines. Notably, these PCA-suppressive effects required the presence of dermal MCs and their expression of VDR. Taken together, data presented in this thesis provide evidence that 1α,25(OH)₂D₃ and 25OHD₃, the latter likely via its conversion to the active metabolite by MCs, can suppress IgE + sAg-mediated MC activation in a VDR-dependent manner both in vitro and in vivo. This suggests the therapeutic potential for various VitD₃ analogues to treat MC-dependent IgE-associated allergic disorders. |
Advisor: | Grimbaldeston, Michele McColl, Shaun Reuss Lopez, Angel Francisco |
Dissertation Note: | Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2014 |
Keywords: | mast cell; vitamin D3; allergic responses; immunoregulatory |
Provenance: | This electronic version is made publicly available by the University of Adelaide in accordance with its open access policy for student theses. Copyright in this thesis remains with the author. This thesis may incorporate third party material which has been used by the author pursuant to Fair Dealing exceptions. If you are the owner of any included third party copyright material you wish to be removed from this electronic version, please complete the take down form located at: http://www.adelaide.edu.au/legals |
Appears in Collections: | Research Theses |
Files in This Item:
File | Description | Size | Format | |
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01front.pdf | 277 kB | Adobe PDF | View/Open | |
02whole.pdf | 5.92 MB | Adobe PDF | View/Open | |
Permissions Restricted Access | Library staff access only | 276.17 kB | Adobe PDF | View/Open |
Restricted Restricted Access | Library staff access only | 5.92 MB | Adobe PDF | View/Open |
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