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Transcriptomic analysis of vitamin D responses in uterine and peripheral NK cells
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J A Tamblyn
J A Tamblyn
Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
Centre for Women’s & Newborn Health, Birmingham Health Partners, Birmingham Women’s & Children’s Foundation Hospital, Edgbaston, Birmingham, UK
Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
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Centre for Women’s & Newborn Health, Birmingham Health Partners, Birmingham Women’s & Children’s Foundation Hospital, Edgbaston, Birmingham, UK
Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
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L E Jeffery
L E Jeffery
Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
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R Susarla
R Susarla
Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
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D M Lissauer
D M Lissauer
Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
Centre for Women’s & Newborn Health, Birmingham Health Partners, Birmingham Women’s & Children’s Foundation Hospital, Edgbaston, Birmingham, UK
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Centre for Women’s & Newborn Health, Birmingham Health Partners, Birmingham Women’s & Children’s Foundation Hospital, Edgbaston, Birmingham, UK
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S L Coort
S L Coort
Department of Bioinformatics-BiGCaT, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands
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A Muñoz Garcia
A Muñoz Garcia
Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
Department of Bioinformatics-BiGCaT, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands
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Department of Bioinformatics-BiGCaT, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands
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K Knoblich
K Knoblich
Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
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A L Fletcher
A L Fletcher
Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
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J N Bulmer
J N Bulmer
Reproductive and Vascular Biology Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
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M D Kilby
M D Kilby
Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
Centre for Women’s & Newborn Health, Birmingham Health Partners, Birmingham Women’s & Children’s Foundation Hospital, Edgbaston, Birmingham, UK
Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
Fetal Medicine Centre, Birmingham Women’s & Children’s Foundation Trust, Edgbaston, Birmingham, UK
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Centre for Women’s & Newborn Health, Birmingham Health Partners, Birmingham Women’s & Children’s Foundation Hospital, Edgbaston, Birmingham, UK
Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
Fetal Medicine Centre, Birmingham Women’s & Children’s Foundation Trust, Edgbaston, Birmingham, UK
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M Hewison
M Hewison
Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
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Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK
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Vitamin D deficiency is prevalent in pregnant women and is associated with adverse pregnancy outcomes, in particular disorders of malplacentation. The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), is a potent regulator of innate and adaptive immunity, but its immune effects during pregnancy remain poorly understood. During early gestation, the predominant immune cells in maternal decidua are uterine natural killer cells (uNK), but the responsivity of these cells to 1,25(OH)2D3 is unknown despite high levels of 1,25(OH)2D3 in decidua. Transcriptomic responses to 1,25(OH)2D3 were characterised in paired donor uNK and peripheral natural killer cells (pNK) following cytokine (CK) stimulation. RNA-seq analyses indicated 911 genes were differentially expressed in CK-stimulated uNK versus CK-stimulated pNK in the absence of 1,25(OH)2D3, with predominant differentially expressed pathways being associated with glycolysis and transforming growth factor β (TGFβ). RNA-seq also showed that the vitamin D receptor (VDR) and its heterodimer partner retinoid X receptor were differentially expressed in CK-stimulated uNK vs CK-stimulated pNK. Further analyses confirmed increased expression of VDR mRNA and protein, as well as VDR-RXR target in CK-stimulated uNK. RNA-seq analysis showed that in CK-stimulated pNK, 1,25(OH)2D3 induced 38 and suppressed 33 transcripts, whilst in CK-stimulated uNK 1,25(OH)2D3 induced 46 and suppressed 19 genes. However, multiple comparison analysis of transcriptomic data indicated that 1,25(OH)2D3 had no significant overall effect on gene expression in either CK-stimulated pNK or uNK. These data indicate that CK-stimulated uNK are transcriptionally distinct from pNK and, despite expressing abundant VDR, neither pNK nor uNK are sensitive targets for vitamin D.
Supplementary Materials
- Supplemental Dataset 1 Pathway analysis of differential gene expression in CK Summary of WikiPathways data-base analysis for CK uNK versus CK pNK. Frequency of significant differentially-expressed genes (p-value <0.05, Z-Score >1.96), based on Z score.
- Supplemental Table 1. Summary of decidua donor demographic analysis. Data show: Identification number (ID), maternal age, body mass index (BMI), ethnicity, gestational age at surgical termination of pregnancy (sTOP) (w; weeks), smoking status (yes [Y] / no [N] - total / day), gravida and parity (G/P) with obstetric history; living, stillbirth, miscarriage, TOP.
- Supplemental Figure 1
- Supplemental Figure 2
- Supplemental Figure 3
- Supplemental Figure 4
- Supplemental Figure 5
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