Abstract
Peripheral blood mononuclear cells (PBMCs) belong to the innate and adaptive immune system and are highly sensitive and responsive to changes in their systemic environment. In this study, we focused on the time course of transcriptional changes in freshly isolated human PBMCs 4, 8, 24 and 48 h after onset of stimulation with the active vitamin D metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3). Taking all four time points together, 662 target genes were identified and segregated either by time of differential gene expression into 179 primary and 483 secondary targets or by driver of expression change into 293 direct and 369 indirect targets. The latter classification revealed that more than 50% of target genes were primarily driven by the cells' response to ex vivo exposure than by the nuclear hormone and largely explained its down-regulatory effect. Functional analysis indicated vitamin D’s role in the suppression of the inflammatory and adaptive immune response by down-regulating ten major histocompatibility complex class II genes, five alarmins of the S100 calcium binding protein A family and by affecting six chemokines of the C-X-C motif ligand family. Taken together, studying time-resolved responses allows to better contextualize the effects of vitamin D on the immune system.
Highlights
Academic Editor: Cristoforo ComiVitamin D3 is a micronutrient that is either produced endogenously in UV-B exposed skin [1] or taken up by diet as well as direct supplementation [2]
Classical pairwise comparison of time-matched treated versus control cells detected 10 and 179 differentially expressed genes at the early time points 4 and 8 h (fold change (FC) > 1.5, false discovery rate (FDR) < 0.05, glmTreat test) as well as 466 and 341 genes at time points 24 and 48 h (FC > 2, FDR < 0.05) (Figure 1A and Table S1)
The 466 target genes found after 24 h stimulation with 1,25(OH)2 D3 showed more than 85% overlap with the 676 and 625 vitamin D target genes identified in Peripheral blood mononuclear cells (PBMCs) from one [32] or five individuals [33] treated under the same protocol and the 1203 genes highlighted in THP-1 cells [19] (Figure S1)
Summary
Academic Editor: Cristoforo ComiVitamin D3 is a micronutrient that is either produced endogenously in UV-B exposed skin [1] or taken up by diet as well as direct supplementation [2]. The evolutionarily oldest role of vitamin D is to maintain energetic and survival homeostasis [3], while its physiologically best known function is the homeostasis of calcium levels being critical for bone mineralization [4]. Another function of vitamin D is the modulation of the immune system [5]. The biological function of vitamin D3 in health and disease is directly linked to 1,25(OH) D3 -dependent changes of the transcriptome in VDR expressing cells [15]. Since primary cells are far closer to the human in vivo situation, PBMCs are an attractive alternative to THP-1 cells and accessible with
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