Griffin, Matthew D.

The NF-κB component RelB is essential for dendritic cell (DC) differentiation and maturation. The vitamin D receptor (VDR) is a nuclear receptor that mediates inhibition of DC maturation and transcriptional repression of relB after engagement of its ligand, 1α,25-dihydroxyvitamin D 3 , or related analogs (D 3 analogs). Ligand-dependent relB suppression was abolished by a histone deacetylase (HDAC) inhibitor. Constitutive association of VDR with the relB promoter was demonstrated in DCs by chromatin immunoprecipitation. Promoter binding by VDR was enhanced by ligand and reduced by LPS. Association of HDAC3 and HDAC1 with the relB VDR-binding site was observed, but only HDAC3 was reciprocally modulated by D 3 analog and LPS. Overexpression of HDAC3 caused relB promoter suppression, increased sensitivity to D 3 analog, and resistance to LPS. Depletion of HDAC3 attenuated relB suppression by D 3 analog. In vivo , D 3 analog resulted in reduced RelB in DCs from VDR WT mice but not VDR knockout mice. Other NF-lation of RelB and c-Rel in control animals. We conclude that vitamin D-regulated relB transcription in DCs is controlled by chromatin remodeling by means of recruitment of complexes including HDAC3.

▪ Abstract It has been a little more than 20 years since the first appreciation that the biologically active hormonal form of the secosteroid vitamin D—classically categorized as a regulator of calcium/phosphorous metabolism and bone mineralization—can exert effects on cells of the immune system. Since then a substantial literature has accumulated to suggest that these effects are exerted on multiple immune cell types, are predominantly suppressive at pharmacologic levels, and are potent enough to have true therapeutic potential in the management or prevention of immune-mediated diseases. Less clear at present, however, are the physiological roles played by the vitamin D endocrine system in the regulation of normal and abnormal immune responses. In this review, an appraisal of the current understanding of vitamin D–mediated immune regulation is presented that emphasizes progress towards its clinical application as well as the manner in which emerging models of normal immune function may facilitate a more complete understanding of its physiologic significance.

Dendritic cells (DCs) play a central role in regulating immune activation and responses to self. DC maturation is central to the outcome of antigen presentation to T cells. Maturation of DCs is inhibited by physiological levels of 1α,25 dihydroxyvitamin D 3 [1α,25(OH) 2 D 3 ] and a related analog, 1α,25(OH) 2 -16-ene-23-yne-26,27-hexafluoro-19-nor-vitamin D 3 (D 3 analog). Conditioning of bone marrow cultures with 10 −10 M D 3 analog resulted in accumulation of immature DCs with reduced IL-12 secretion and without induction of transforming growth factor β1. These DCs retained an immature phenotype after withdrawal of D 3 analog and exhibited blunted responses to maturing stimuli (CD40 ligation, macrophage products, or lipopolysaccharide). Resistance to maturation depended on the presence of the 1α,25(OH) 2 D 3 receptor (VDR). In an in vivo model of DC-mediated antigen-specific sensitization, D 3 analog-conditioned DCs failed to sensitize and, instead, promoted prolonged survival of subsequent skin grafts expressing the same antigen. To investigate the physiologic significance of 1α,25(OH) 2 D 3 /VDR-mediated modulation of DC maturity we analyzed DC populations from mice lacking VDR. Compared with wild-type animals, VDR-deficient mice had hypertrophy of subcutaneous lymph nodes and an increase in mature DCs in lymph nodes but not spleen. We conclude that 1α,25(OH) 2 D 3 /VDR mediates physiologically relevant inhibition of DC maturity that is resistant to maturational stimuli and modulates antigen-specific immune responses in vivo .