Unbiased genomic screening analyses have highlighted novel immunomodulatory properties of the active form of vitamin D, 1,25-dihydroxyvitamin D (1,25(OH)2D). However, clearer interpretation of the resulting gene expression data is limited by cell model specificity. The aim of the current study was to provide a broader perspective on common gene regulatory pathways associated with innate immune responses to 1,25(OH)2D, through systematic re-interrogation of existing gene expression databases from multiple related monocyte models (the THP-1 monocytic cell line (THP-1), monocyte-derived dendritic cells (DCs) and monocytes). Vitamin D receptor (VDR) expression is common to multiple immune cell types, and thus, pathway analysis of gene expression using data from multiple related models provides an inclusive perspective on the immunomodulatory impact of vitamin D. A bioinformatic workflow incorporating pathway analysis using PathVisio and WikiPathways was utilized to compare each set of gene expression data based on pathway-level context. Using this strategy, pathways related to the TCA cycle, oxidative phosphorylation and ATP synthesis and metabolism were shown to be significantly regulated by 1,25(OH)2D in each of the repository models (Z-scores 3.52–8.22). Common regulation by 1,25(OH)2D was also observed for pathways associated with apoptosis and the regulation of apoptosis (Z-scores 2.49–3.81). In contrast to the primary culture DC and monocyte models, the THP-1 myelomonocytic cell line showed strong regulation of pathways associated with cell proliferation and DNA replication (Z-scores 6.1–12.6). In short, data presented here support a fundamental role for active 1,25(OH)2D as a pivotal regulator of immunometabolism.
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Amadeo Muñoz Garcia, Martina Kutmon, Lars Eijssen, Martin Hewison, Chris T Evelo, and Susan L Coort
V Vivat, D Gofflo, T Garcia, J-M Wurtz, W Bourguet, D Philibert, and H Gronemeyer
ABSTRACT
The natural ligands of the progesterone (PR) and androgen (AR) receptors, progesterone and testosterone, differ only by their 17β-substitution. To identify within the AR and PR ligand-binding domains (LBDs) the sequences responsible for the differential recognition of these ligands, chimeric LBDs assembled from five homologous AR/PR 'cassettes' linked to the GAL4-DNA binding domain were constructed, and their ligand binding and transactivation characteristics were determined. Replacing the central cassette 3 of PR by that of AR generated a progesterone- and testosterone-responsive PR LBD with the AR residues 788-RHLS-791 being specifically involved in testosterone recognition, while the introduction of the C-terminal PR cassette 5 into AR conferred progestin responsiveness onto the AR LBD. These results suggest that residues within AR 788-RHLS-791 interact with the testosterone 17β-OH, while PR cassette 5 apparently contains the amino acid(s) specifically involved in the recognition of the progesterone 17β-acetyl group. However, ligand binding and transactivation by these chimeras were significantly decreased compared with those of the parental LBDs, indicating that residues located outside of these cassettes contribute to the proper positioning of the steroids in the AR and PR ligand-binding pockets (LBPs). Indeed, certain AR/PR chimeras acquired efficient ligand binding, but were unable to transactivate, indicating that the ligand was improperly bound in the chimeric LBP and could not induce the conformational changes leading to a transcriptionally competent activation function (AF-2) within the LBD. The properties of the various LBD chimeras are discussed in view of the recently solved three-dimensional structures of the retinoid X receptor α apo- and retinoic acid receptor γ holo-LBDs.
