Regulation of relB in dendritic cells by means of modulated association of vitamin D receptor and histone deacetylase 3 with the promoter

摘要

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 immu-noprecipitation. 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-κB family members were unaffected. In vivo RelB suppression was prevented by concomitant administration of HDAC inhibitor, which also resulted in up-regulation 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.