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

Xiangyang Dong, Ward Lutz, Tania M. Schroeder, Lori A. Bachman, Jennifer J. Westendorf, Rajiv Kumar, Matthew D. Griffin

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

Abstract

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 D3, or related analogs (D3 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 D3 analog and LPS. Overexpression of HDAC3 caused relB promoter suppression, increased sensitivity to D3 analog, and resistance to LPS. Depletion of HDAC3 attenuated relB suppression by D3 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.

Original languageEnglish (US)
Pages (from-to)16007-16012
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number44
DOIs
StatePublished - Nov 1 2005

Keywords

  • Antigen presentation
  • Chromatin remodeling immunity
  • NF-κB
  • Nuclear receptors

ASJC Scopus subject areas

  • General

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