Journal
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
Volume 189, Issue -, Pages 1-9Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jsbmb.2019.01.014
Keywords
Immune regulation; IL-10; alpha-1-Antitrypsin; Complement; C3a
Funding
- Medical Research Council (MRC)
- Asthma UK Centre for Allergic Mechanisms of Asthma
- MRC Research Grant [G1002165]
- Medical Research Council Centre for Transplantation, KCL
- Alpha -1 Foundation
- Department of Health, National Institute for Health Research comprehensive Biomedical Research Centre
- King's College London
- King's College Hospital NHS Foundation Trust
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [ZIAHL006223] Funding Source: NIH RePORTER
- MRC [G1002165] Funding Source: UKRI
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Studies to identify novel immune-regulatory functions of active vitamin D (1,25(OH)(2)D3) in human CD4(+) T cells revealed that 1,25(OH)(2)D3 potently induced expression of the gene SERPINA1, encoding the anti-protease alpha-1-antitrypsin. We confirmed alpha-1-antitrypsin protein expression by 1,25(OH)(2)D3-treated CD4(+) T cells, but not in CD8(+) T cells or monocytes. alpha-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 alpha-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. alpha-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 alpha-1-antitrypsin contained C3a. Surface Plasmon Resonance and Microscale Thermophoresis demonstrated alpha-1-antitrypsin binding to C3a. Addition of C3a to CD4(+) T cells cultured with recombinant alpha-1-antitrypsin restored induction of IL-10, whereas neutralisation of C3a abrogated IL-10 induced by plasma-derived alpha-1-antitrypsin. To interrogate an endogenous role for the alpha-1-antitrypsin-C3a axis in 1,25(OH)(2)D3-driven CD4(+) T cell IL-10 synthesis, we treated cells from healthy or alpha-1-antitrypsin-deficient individuals (which transcribe SERPINA1 but do not secrete protein) with 1,25(OH)(2)D3. A significant correlation was identified between SERPINA1 and IL10 gene expression in healthy donor CD4(+) T cells, which was absent in cells from alpha-1-antitrypsin-deficient individuals. Therefore, alpha-1-antitrypsin is required for 1,25(OH)(2)D3-induced IL-10 expression in CD4(+) T cells, interacting with C3a to drive IL-10 expression.
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