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*Compound via MeSH
*Substance via MeSH
Hazardous Substances DB
*1,25-DIHYDROXYCHOLECALCIFEROL
The Journal of Immunology, 2003, 170: 5382-5390.
Copyright © 2003 by The American Association of Immunologists

Differential Regulation of Vitamin D Receptor and Its Ligand in Human Monocyte-Derived Dendritic Cells1

Martin Hewison*, Lisa Freeman{dagger}, Susan V. Hughes*, Katie N. Evans*, Rosemary Bland*, Aristides G. Eliopoulos{ddagger}, Mark D. Kilby§, Paul A. H. Moss{dagger} and Ronjon Chakraverty2,{dagger}

Departments of * Medical Sciences, {dagger} Hematology, {ddagger} Cancer Studies, and § Reproductive and Child Health, University of Birmingham, Edgbaston, Birmingham, United Kingdom

The functions of dendritic cells (DCs) are tightly regulated such that protective immune responses are elicited and unwanted immune responses are prevented. 1{alpha}25-dihydroxyvitamin D3 (1{alpha}25(OH)2D3) has been identified as a major factor that inhibits the differentiation and maturation of DCs, an effect dependent upon its binding to the nuclear vitamin D receptor (VDR). Physiological control of 1{alpha}25(OH)2D3 levels is critically dependent upon 25-hydroxyvitamin D3-1{alpha}-hydroxylase (1{alpha}OHase), a mitochondrial cytochrome P450 enzyme that catalyzes the conversion of inactive precursor 25-hydroxyvitamin D3 (25(OH)D3) to the active metabolite 1{alpha}25(OH)2D3. Using a human monocyte-derived DC (moDC) model, we have examined the relationship between DC VDR expression and the impact of exposure to its ligand, 1{alpha}25(OH)2D3. We show for the first time that moDCs are able to synthesize 1{alpha}25(OH)2D3 in vitro as a consequence of increased 1{alpha}OHase expression. Following terminal differentiation induced by a diverse set of maturation stimuli, there is marked transcriptional up-regulation of 1{alpha}OHase leading to increased 1{alpha}OHase enzyme activity. Consistent with this finding is the observation that the development and function of moDCs is inhibited at physiological concentrations of the inactive metabolite 25(OH)D3. In contrast to 1{alpha}OHase, VDR expression is down-regulated as monocytes differentiate into immature DCs. Addition of 1{alpha}25(OH)2D3 to moDC cultures at different time points indicates that its inhibitory effects are greater in monocyte precursors than in immature DCs. In conclusion, differential regulation of endogenous 1{alpha}25(OH)2D3 ligand and its nuclear receptor appear to be important regulators of DC biology and represent potential targets for the manipulation of DC function.




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