Session Type: Abstract Submissions (ACR)
Vitamin D has suppressive effects on autoimmune diseases, such as rheumatoid arthritis (RA). One important mechanism of disease suppression by vitamin D is inhibition of Th17 cytokines and the Th17 transcription factor RORγt. On the other hand, vitamin D induces IL-4 and GATA3. Since GATA3 overexpression inhibits experimental Th17-mediated autoimmunity, we studied the contribution of GATA3 in vitamin D-mediated suppression of Th17 polarization.
We first sorted CD4+ T cells from the spleen of naïve DBA-1 mice and DBA-1 mice immunized with collagen type II (CII) and cultured them under T helper cell polarizing conditions with or without 1,25(OH)2D3, the active form of vitamin D. Furthermore, splenic CD4+ T cells are sorted from wild-type and CD2-GATA3 transgenic mice and cultured under these conditions. Finally, we performed gene-expression profiling on CCR6+cells from treatment-naïve early RA patients.
In cultures of CD4+ T cells from naïve and CII-immunized mice, 1,25(OH)2D3 inhibits Th17 polarization while inducing IL-4 and GATA3 expression. IL-4 inhibition partly reversed the vitamin D-mediated inhibition of Th17 polarization. To study the role of GATA3, we compared CD4+ T cells from wild-type and CD2-GATA3 transgenic mice after culture under Th17 polarizing conditions. In these cultures 1,25(OH)2D3 reduces Th17 differentiation, but the effect of GATA3 overexpression is stronger. Interestingly, combining GATA3 overexpression and 1,25(OH)2D3 treatment reduced IL-17A and RORγt expression even further. Subsequent analysis of gene expression in wild-type CD4+ T cells cultured under Th17 polarizing conditions showed that NFAT-C2, which is involved in IL-17A production, was downregulated by 1,25(OH)2D3. In addition, gene expression analysis in CCR6+ T cells from patients with RA showed that 1,25(OH)2D3also inhibits Th17 cytokine and RORγt expression in humans, while inducing IL-4 and GATA3 expression.
These data show that vitamin D-mediated regulation of Th17 polarization occurs through GATA3-dependent mechanisms, including direct effects on RORγt expression and IL-4-mediated inhibition of Th17 polarization. Moreover, GATA3-independent mechanisms are involved that may include modulation of NFAT-C2. These mechanisms may play a role in the suppressive effect of vitamin D on RA disease activity.
J. P. van Hamburg,
A. M. Mus,
P. S. Asmawidjaja,
J. van Leeuwen,
R. W. Hendriks,
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ACR Meeting Abstracts - http://acrabstracts.org/abstract/125oh2d3-inhibits-th17-cytokine-production-and-ror%ce%b3t-expression-through-gata3il4-dependent-and-independent-mechanisms/