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

Abstract

The functions of dendritic cells (DCs) are tightly regulated such that protective immune responses are elicited and unwanted immune responses are prevented. 1α25-dihydroxyvitamin D3 (1α25(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 1α25(OH)2D3 levels is critically dependent upon 25-hydroxyvitamin D3-1α-hydroxylase (1αOHase), a mitochondrial cytochrome P450 enzyme that catalyzes the conversion of inactive precursor 25-hydroxyvitamin D3 (25(OH)D3) to the active metabolite 1α25(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, 1α25(OH)2D3. We show for the first time that moDCs are able to synthesize 1α25(OH)2D3 in vitro as a consequence of increased 1αOHase expression. Following terminal differentiation induced by a diverse set of maturation stimuli, there is marked transcriptional up-regulation of 1αOHase leading to increased 1αOHase 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 1αOHase, VDR expression is down-regulated as monocytes differentiate into immature DCs. Addition of 1α25(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 1α25(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.

1,25‐dihydroxyvitamin D3 promotes IL‐10 production in human B cells

“…CYP1a expression in activated macrophages, dendritic cells and T cells enables them to synthesize functional vitamin D [25][26][27]. Here we show that human B cells expressed cyp1a mRNA, when activated by anti-CD40 and IL-4, which was increased by signaling from BCR and TLR-9 (Fig.…”

“…Extrarenal production of calcitriol has been shown in primary human myeloid cells. CYP1a expression is induced during maturation from monocytic cells into mature dendritic cells [25,26]. Recently, it has been shown that calcitriol can be produced by T cells [27] and evidence was given also for B cells [44].…”

Vitamin D immunoregulation through dendritic cells

“…The properties of these in‐vitro ‐generated moDC were substantially altered when 1,25‐OH‐VD3 was included during their differentiation: VD3‐‘tolerized’ moDC were less effective in their induction of T‐cell proliferation,20 but rather induced Treg cells that promoted transplant tolerance 21, 22. MoDC generated in the presence of 1,25‐OH‐VD3 were less capable of producing interleukin‐12 (IL‐12) p70,23 but rather secreted IL‐10 14, 24. These cells also possess decreased densities of the co‐stimulatory molecules CD80 and CD86 and of the antigen‐presenting MHCII complex 20, 23.…”

“…MoDC generated in the presence of 1,25‐OH‐VD3 were less capable of producing interleukin‐12 (IL‐12) p70,23 but rather secreted IL‐10 14, 24. These cells also possess decreased densities of the co‐stimulatory molecules CD80 and CD86 and of the antigen‐presenting MHCII complex 20, 23. Hence, with all three pillars of T‐cell activation being hampered by 1,25‐OH‐VD3 modulation of moDC development, its potential as a tolerance‐inducing agent for DC therapy, and as a therapeutic immune modulator against diseases with underlying inappropriate or overwhelming inflammation, was recognized 11, 18…”

“…T‐cell hyporesponsiveness induction or metabolic switches),23, 32 but these serum 25‐OH‐VD3 levels are too low for the autocrine/paracrine induction of CCR10 on T cells in moDC : T‐cell co‐cultures67 (Fig. 2).…”