title: Vitamin D receptor-mediated suppression of RelB in antigen presenting cells: a paradigm for ligand-augmented negative transcriptional regulation.
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 1alpha,25(OH)D3 or synthetic D3 analogs we observed that expression of the NF-kappaB 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/RXR alpha 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.
authors: Department of Internal Medicine, Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA. griffin.matthew@mayo.edu
authors: Matthew D
authors: MD
authors: Griffin
authors: Xiangyang
authors: X
authors: Dong
authors: Rajiv
authors: R
authors: Kumar
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism*; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding / Q000187:drug effects; D018167:Receptors, Calcitriol / Q000378:metabolism*; D020218:Response Elements / Q000502:physiology; D047490:Retinoid X Receptor alpha / Q000378:metabolism; D051841:Transcription Factor RelB / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D014815:Vitamins / Q000378:metabolism / Q000494:pharmacology; D000099186:Histone Deacetylase 3
chemical_list: D002117:Calcitriol; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases; D008024:Ligands; D018167:Receptors, Calcitriol; D047490:Retinoid X Receptor alpha; D051841:Transcription Factor RelB; D014815:Vitamins; D000099186:Histone Deacetylase 3; C497593:RELB protein, human; C110550:HDAC1 protein, human