期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 278, 期 49, 页码 49378-49385出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M308448200
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资金
- NIDDK NIH HHS [R01 DK025409, DK25409, T32DK07013, R01 DK058546, DK58546, DK59505] Funding Source: Medline
The nuclear factor-kappaB (NF-kappaB) protein RelB plays a unique role in dendritic cell ( DC) function and, as such, is an important regulator of antigen presentation and immune regulation. In this study, inhibition of RelB expression in DCs exposed to an analog of the active form of vitamin D-3 (1alpha, 25-dihydroxyvitamin D-3 (1alpha, 25( OH)(2)D-3)) was observed and shown to be mediated by the vitamin D receptor (VDR). Potential vitamin D response elements were identified within promoter regions of human and mouse relB genes. In gel shift experiments, these motifs specifically bound VDR . retinoid X receptor-alpha complexes. Reporter assays confirmed that transcriptional activity of human and mouse relB promoters was inhibited by 1alpha,25-(OH)(2)D-3 agonists in a DC-derived cell line. The inhibition was abolished by mutagenesis of the putative vitamin D response elements and was enhanced by overexpression of VDR. Mutagenesis of NF-kappaB response elements within the relB promoter did not affect the magnitude of 1alpha, 25-(OH)(2)D-3 analog-mediated inhibition, ruling out an indirect effect on NF-kappaB signaling. Glucocorticoid caused additional inhibition of relB promoter activity when combined with the 1alpha, 25-(OH)(2)D-3 analog. This effect was dependent on the integrity of the NF-kappaB response elements, suggesting separate regulatory mechanisms for the two steroid pathways on this promoter. We conclude that relB is a direct target for 1alpha, 25-(OH)(2)D-3-mediated negative transcriptional regulation via binding of VDR . retinoid X receptor-alpha to discrete DNA motifs. This mechanism has important implications for the inhibitory effect of 1alpha, 25-(OH)(2)D-3 on DC maturation and for the potential immunotherapeutic use of 1alpha, 25-(OH)(2)D-3 analogs alone or combined with other agents.
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