Endocrine Abstracts (2003) 5 P224

Differential regulation of vitamin D receptor and its ligand in human dendritic cells: A paracrine mechanism for regulation of antigen presentation

L Freeman2, K Evans1, SV Hughes1, P Moss2, R Chakraverty2 & M Hewison1

1Division of Medical Sciences, University of Birmingham, Birmingham, UK; 2Division of Haematology, University of Birmingham, Birmingham, UK.

The functions of dendritic cells (DCs) are tightly regulated such that protective immune responses are elicited and unwanted immune responses are prevented. 1,25-dihydroxyvitamin D3 (1,25(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 1,25(OH)2D3 levels is dependent upon the enzyme 25-hydroxyvitamin-D3-1alpha-hydroxylase (1alphaOHase), that catalyzes conversion of inactive precursor 25-hydroxyvitamin-D3 (25(OH)D3) to the active metabolite 1,25(OH)2D3. Using a monocyte-derived DC (moDC) model, we examined the relationship between DC VDR expression and the impact of exposure to its ligand, 1,25(OH)2D3. We show that moDCs are able to synthesize 1,25(OH)2D3 in vitro as a consequence of increased 1(OHase expression and activity (75-fold induction in mRNA and 10-fold increase in protein in mature DC; synthesis of 1,25(OH)2D3 increased from undetectable in peripheral blood mononuclear cells to 50 fmoles/hr/10-6 cells in mature DC). Consistent with this finding is the observation that the development, maturation (CD83, CD86 and class II MHC expression) and allo-stimulatory potential of moDCs (mixed lymphocyte reaction) is inhibited at physiological concentrations of the inactive metabolite 25(OH)D3 (50 nM) as well as active 1,25(OH)2D3 (10 nM). In contrast to 1(OHase, VDR expression is down-regulated as monocytes differentiate and mature into DCs (3-fold decrease in mRNA and nuclear binding of 1,25(OH)2D3). Accordingly, the inhibitory effect of 1,25(OH)2D3 is lost in more mature moDCs. In conclusion, differential regulation of endogenous 1,25(OH)2D3 ligand and its nuclear receptor appear to be important determinants of DC biology. This represents a significant development in our understanding of the impact of vitamin D on immune responses and, in particular, provides a potential target for the manipulation of DC function.

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