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Vitamin D (1,25(OH)2D3) induces ?-1-antitrypsin synthesis by CD4+ T cells, which is required for 1,25(OH)2D3-driven IL-10.

ABSTRACT: Studies to identify novel immune-regulatory functions of active vitamin D (1,25(OH)2D3) in human CD4+ T cells revealed that 1,25(OH)2D3 potently induced expression of the gene SERPINA1, encoding the anti-protease ?-1-antitrypsin. We confirmed ?-1-antitrypsin protein expression by 1,25(OH)2D3-treated CD4+ T cells, but not in CD8+ T cells or monocytes. ?-1-Antitrypsin promotes anti-inflammatory IL-10 synthesis in other immune cell populations. We therefore investigated its immune-regulatory effects in CD4+ T cells. Plasma-derived ?-1-antitrypsin drove IL-10 synthesis by CD4+ T cells, which was not dependent on anti-protease activity, but appeared to require a serum-binding factor, since this could not be achieved with recombinant protein. ?-1-Antitrypsin is reported to bind complement components, which regulate T cell function. A role for this interaction was therefore probed. Plasma-derived, but not recombinant ?-1-antitrypsin contained C3a. Surface Plasmon Resonance and Microscale Thermophoresis demonstrated ?-1-antitrypsin binding to C3a. Addition of C3a to CD4+ T cells cultured with recombinant ?-1-antitrypsin restored induction of IL-10, whereas neutralisation of C3a abrogated IL-10 induced by plasma-derived ?-1-antitrypsin. To interrogate an endogenous role for the ?-1-antitrypsin-C3a axis in 1,25(OH)2D3-driven CD4+ T cell IL-10 synthesis, we treated cells from healthy or ?-1-antitrypsin-deficient individuals (which transcribe SERPINA1 but do not secrete protein) with 1,25(OH)2D3. A significant correlation was identified between SERPINA1 and IL10 gene expression in healthy donor CD4+ T cells, which was absent in cells from ?-1-antitrypsin-deficient individuals. Therefore, ?-1-antitrypsin is required for 1,25(OH)2D3-induced IL-10 expression in CD4+ T cells, interacting with C3a to drive IL-10 expression.

SUBMITTER: Dimeloe S

PROVIDER: S-EPMC6525112 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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Vitamin D (1,25(OH)2D3) induces α-1-antitrypsin synthesis by CD4+ T cells, which is required for 1,25(OH)2D3-driven IL-10.

Dimeloe Sarah S Rice Louise V LV Chen Hebe H Cheadle Charlotte C Raynes John J Pfeffer Paul P Lavender Paul P Richards David F DF Nyon Mun Peak MP McDonnell James M JM Kemper Claudia C Gooptu Bibek B Hawrylowicz Catherine M CM

The Journal of steroid biochemistry and molecular biology 20190125

Studies to identify novel immune-regulatory functions of active vitamin D (1,25(OH)2D3) in human CD4+ T cells revealed that 1,25(OH)2D3 potently induced expression of the gene SERPINA1, encoding the anti-protease α-1-antitrypsin. We confirmed α-1-antitrypsin protein expression by 1,25(OH)2D3-treated CD4+ T cells, but not in CD8+ T cells or monocytes. α-1-Antitrypsin promotes anti-inflammatory IL-10 synthesis in other immune cell p ...[more]

PMID: 30690074

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Project description:A novel pathway of vitamin D activation by CYP11A has previously been elucidated. To define the mechanism of action of its major dihydroxy-products, we tested the divergence and overlap between the gene expression profiles of human epidermal keratinocytes treated with either CYP11A1-derived 20,23(OH)₂D3 or classical 1,25(OH)₂D3. Both secosteroids have significant chemical similarity with the only differences being the positions of the hydroxyl groups. mRNA was isolated and examined by microarray analysis using Illumina's HumanWG-6 chip/arrays and subsequent bioinformatics analyses. Marked differences in the up- and downregulated genes were observed between 1,25(OH)₂D3- and 20,23(OH)₂D3-treated cells. Hierarchical clustering identified both distinct, opposite and common (overlapping) gene expression patterns. CYP24A1 was a common gene strongly activated by both compounds, a finding confirmed by qPCR. Ingenuity pathway analysis identified VDR/RXR signaling as the top canonical pathway induced by 1,25(OH)₂D3. In contrast, the top canonical pathway induced by 20,23(OH)₂D3 was AhR, with VDR/RXR being the second nuclear receptor signaling pathway identified. QPCR analyses validated the former finding by revealing that 20,23(OH)₂D3 stimulated CYP1A1 and CYP1B1 gene expression, effects located downstream of AhR. Similar stimulation was observed with 20(OH)D3, the precursor to 20,23(OH)₂D3, as well as with its downstream metabolite, 17,20,23(OH)₃D3. Using a Human AhR Reporter Assay System we showed marked activation of AhR activity by 20,23(OH)₂D3, with weaker stimulation by 20(OH)D3. Finally, molecular modeling using an AhR LBD model predicted vitamin D3 hydroxyderivatives to be good ligands for this receptor. Thus, our microarray, qPCR, functional studies and molecular modeling indicate that AhR is the major receptor target for 20,23(OH)₂D3, opening an exciting area of investigation on the interaction of different vitamin D3-hydroxyderivatives with AhR and the subsequent downstream activation of signal transduction pathways in a cell-type-dependent manner.

Dataset Information

Vitamin D (1,25(OH)2D3) induces ?-1-antitrypsin synthesis by CD4+ T cells, which is required for 1,25(OH)2D3-driven IL-10.

Publications

Vitamin D (1,25(OH)<sub>2</sub>D3) induces α-1-antitrypsin synthesis by CD4<sup>+</sup> T cells, which is required for 1,25(OH)<sub>2</sub>D3-driven IL-10.

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