Direct Transcriptional Regulation of RelB by 1α,25-Dihydroxyvitamin D3 and Its Analogs

  • Dong X
  • Craig T
  • Xing N
  • et al.
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Abstract

The nuclear factor-B (NF-B) 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 (1,25-dihydroxyvitamin D 3 (1,25-(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 VDRretinoid X receptor-complexes. Reporter assays confirmed that transcriptional activity of human and mouse relB promoters was inhibited by 1,25-(OH) 2 D 3 agonists in a DC-derived cell line. The inhibition was abolished by mu-tagenesis of the putative vitamin D response elements and was enhanced by overexpression of VDR. Mutagen-esis of NF-B response elements within the relB promoter did not affect the magnitude of 1,25-(OH) 2 D 3 an-alog-mediated inhibition, ruling out an indirect effect on NF-B signaling. Glucocorticoid caused additional inhibition of relB promoter activity when combined with the 1,25-(OH) 2 D 3 analog. This effect was dependent on the integrity of the NF-B response elements, suggesting separate regulatory mechanisms for the two steroid pathways on this promoter. We conclude that relB is a direct target for 1,25-(OH) 2 D 3-mediated negative transcriptional regulation via binding of VDRretinoid X receptor-to discrete DNA motifs. This mechanism has important implications for the inhibi-tory effect of 1,25-(OH) 2 D 3 on DC maturation and for the potential immunotherapeutic use of 1,25-(OH) 2 D 3 analogs alone or combined with other agents.

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Dong, X., Craig, T., Xing, N., Bachman, L. A., Paya, C. V., Weih, F., … Griffin, M. D. (2003). Direct Transcriptional Regulation of RelB by 1α,25-Dihydroxyvitamin D3 and Its Analogs. Journal of Biological Chemistry, 278(49), 49378–49385. https://doi.org/10.1074/jbc.m308448200

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