期刊
IMMUNOBIOLOGY
卷 217, 期 12, 页码 1292-1300出版社
ELSEVIER GMBH
DOI: 10.1016/j.imbio.2012.07.018
关键词
Macrophage; Vitamin D; Inflammation; Type I diabetes
类别
资金
- Fund for Scientific Research Flanders (FWO-Vlaanderen) [G.0734.10]
- University of Leuven (KU Leuven) [GOA 2009/10]
- Belgian Government (Interuniversity Attraction Poles of the Belgian Federal Science Policy Office) [P6/40]
- Dutch Diabetes Foundation (DFN)
- European Community with acronym NAIMIT [241447]
- Juvenile Diabetes Research Foundation [JDRF 17-2011-524]
- KU Leuven
The vitamin D receptor (VDR) is a hormone nuclear receptor regulating bone and calcium homeostasis. Studies revealing the expression of VDR on immune cells point toward a role for VDR-dependent signaling pathways in immunity. Here we verified the ability of the natural VDR ligand, 1,25-dihydroxyvitamin D-3 (1,25(OH)(2)D-3) to interfere in inflammatory and T cell stimulatory capacity of macrophages, in particular within a chronic inflammatory disease features of experimental type 1 diabetes (T1D). We demonstrated that VDR is constitutively expressed in macrophages and both the levels of VDR and its downstream targets, are clearly induced by 1,25(OH)(2)D-3. In control mice, macrophage programming with 1,25(OH)(2)D-3 partially abrogated the activation-provoked expression of IL-12p40, TNF alpha and iNOS as well as the effector T cell-recruiting chemokines, CXCL9, CXCL10 and CXCL11. Targeting VDR signaling in macrophages counteracted their T-cell stimulatory ability despite essentially unaltered expression of antigen-presenting and costimulatory molecules. Furthermore, even in non-obese diabetic (NOD) mice, where macrophages/monocytes featured a heightened responsiveness toward danger signals and a superior T cell stimulatory capacity, 1,25(OH)2D3 successfully curtailed these basic macrophage-mediated functions. Interestingly, the inhibitory action of the active compound was associated with an IL-10-dependent mechanism since 1,25(OH)(2)D-3-treatment of IL-10-deficient macrophages failed to reproduce the characteristic repression on inflammatory mediators or T cell proliferation. Combined, these results highlight the possible therapeutic applicability of this natural immunomodulator, due to its ability to counteract macrophage inflammatory and T cell-activating pathways. (C) 2012 Elsevier GmbH. All rights reserved.
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