TY - JOUR
T1 - Vitamin D (1,25(OH) 2 D3) induces α-1-antitrypsin synthesis by CD4 + T cells, which is required for 1,25(OH) 2 D3-driven IL-10
AU - Dimeloe, Sarah
AU - Rice, Louise V.
AU - Chen, Hebe
AU - Cheadle, Charlotte
AU - Raynes, John
AU - Pfeffer, Paul
AU - Lavender, Paul
AU - Richards, David F.
AU - Nyon, Mun Peak
AU - McDonnell, James M.
AU - Kemper, Claudia
AU - Gooptu, Bibek
AU - Hawrylowicz, Catherine M.
N1 - Publisher Copyright:
© 2019
PY - 2019/5
Y1 - 2019/5
N2 - 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 α-1-antitrypsin. We confirmed α-1-antitrypsin protein expression by 1,25(OH) 2 D3-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 populations. We therefore investigated its immune-regulatory effects in CD4 + T cells. Plasma-derived α-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. α-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 α-1-antitrypsin contained C3a. Surface Plasmon Resonance and Microscale Thermophoresis demonstrated α-1-antitrypsin binding to C3a. Addition of C3a to CD4 + T cells cultured with recombinant α-1-antitrypsin restored induction of IL-10, whereas neutralisation of C3a abrogated IL-10 induced by plasma-derived α-1-antitrypsin. To interrogate an endogenous role for the α-1-antitrypsin-C3a axis in 1,25(OH) 2 D3-driven CD4 + T cell IL-10 synthesis, we treated cells from healthy or α-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 α-1-antitrypsin-deficient individuals. Therefore, α-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.
AB - 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 α-1-antitrypsin. We confirmed α-1-antitrypsin protein expression by 1,25(OH) 2 D3-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 populations. We therefore investigated its immune-regulatory effects in CD4 + T cells. Plasma-derived α-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. α-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 α-1-antitrypsin contained C3a. Surface Plasmon Resonance and Microscale Thermophoresis demonstrated α-1-antitrypsin binding to C3a. Addition of C3a to CD4 + T cells cultured with recombinant α-1-antitrypsin restored induction of IL-10, whereas neutralisation of C3a abrogated IL-10 induced by plasma-derived α-1-antitrypsin. To interrogate an endogenous role for the α-1-antitrypsin-C3a axis in 1,25(OH) 2 D3-driven CD4 + T cell IL-10 synthesis, we treated cells from healthy or α-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 α-1-antitrypsin-deficient individuals. Therefore, α-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.
UR - http://www.scopus.com/inward/record.url?scp=85061024390&partnerID=8YFLogxK
U2 - 10.1016/j.jsbmb.2019.01.014
DO - 10.1016/j.jsbmb.2019.01.014
M3 - Journal articles
C2 - 30690074
AN - SCOPUS:85061024390
SN - 0960-0760
VL - 189
SP - 1
EP - 9
JO - Journal of Steroid Biochemistry and Molecular Biology
JF - Journal of Steroid Biochemistry and Molecular Biology
ER -
