Gene-Regulatory Potential of 25-Hydroxyvitamin D3 and D2

Abstract

Human peripheral blood mononuclear cells (PBMCs) represent a highly responsive primary tissue that is composed of innate and adaptive immune cells. In this study, we compared modulation of the transcriptome of PBMCs by the vitamin D metabolites 25-hydroxyvitamin D 3 (25(OH)D 3 ), 25(OH)D 2 and 1α,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ). Saturating concentrations of 1,25(OH) 2 D 3 , 25(OH)D 3 and 25(OH)D 2 resulted after 24 h stimulation in a comparable number and identity of target genes, but below 250 nM 25(OH)D 3 and 25(OH)D 2 were largely insufficient to affect the transcriptome. The average EC 50 values of 206 common target genes were 322 nM for 25(OH)D 3 and 295 nM for 25(OH)D 2 being some 600-fold higher than 0.48 nM for 1,25(OH) 2 D 3 . The type of target gene, such as primary/secondary, direct/indirect or up-/down-regulated, had no significant effect on vitamin D metabolite sensitivity, but individual genes could be classified into high, mid and lower responders. Since the 1α-hydroxylase CYP27B1 is very low expressed in PBMCs and early (4 and 8 h) transcriptome responses to 25(OH)D 3 and 25(OH)D 2 were as prominent as to 1,25(OH) 2 D 3 , both vitamin D metabolites may directly control gene expression. In conclusion, at supra-physiological concentrations 25(OH)D 3 and 25(OH)D 2 are equally potent in modulating the transcriptome of PBMCs possibly by directly activating the vitamin D receptor.

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