Vitamin D receptor-mediated suppression of RelB in antigen presenting cells: A paradigm for ligand-augmented negative transcriptional regulation

Matthew D. Griffin, Xiangyang Dong, Rajiv Kumar

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

The immunological effects of vitamin D receptor (VDR) ligands include inhibition of dendritic cell (DC) maturation, suppression of T-helper type 1 (Th1) T-cell responses and facilitation of antigen-specific immune tolerance in vivo. While studying the molecular profile of DCs cultured in the presence of 1α,25(OH)D3 or synthetic D3 analogs we observed that expression of the NF-κB family member RelB, which plays an essential role in DC differentiation and maturation, is selectively suppressed by VDR ligands. Further in vitro and in vivo studies of VDR-mediated RelB suppression indicated that the mechanism for this effect involves direct binding of VDR/RXRα to a defined region of the relB promoter and assembly of a negative regulatory complex containing HDAC3, HDAC1, SMRT and, most likely, other factors. Interestingly, promoter engagement by VDR and HDAC3, but not the other identified components, is enhanced by addition of a VDR ligand and inhibited by a pro-maturational stimulus (LPS) that results in RelB upregulation. Promoter assays in a panel of cell lines suggest that the VDR ligand-dependent component of relB suppression may occur selectively in antigen presenting cells. Cell type-specific, ligand-enhanced negative transcriptional regulation represents a potentially novel paradigm for VDR-controlled genes. In this report we review the experimental data to support such a mechanism for relB regulation in DCs and present a model for the process.

Original languageEnglish (US)
Pages (from-to)218-226
Number of pages9
JournalArchives of Biochemistry and Biophysics
Volume460
Issue number2
DOIs
StatePublished - Apr 15 2007

Keywords

  • Antigen presentation
  • Autoimmunity
  • Co-repressors
  • Dendritic cells
  • Histone deacetylases
  • Immune system
  • Immune tolerance
  • Negative regulation
  • Nuclear factor kappa B, RelB
  • Retinoic acid receptor X
  • Transcription
  • Vitamin D analogs
  • Vitamin D receptor

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology

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