Background and Objectives Vitamin D has suppressive effects on autoimmune diseases, such as rheumatoid arthritis (RA). Regulation of Th17 cell activity is an important mechanism by which vitamin D exerts these effects. Aside from inhibiting Th17 cytokines and the Th17 transcription factor RoRγ t, vitamin D induces IL-4 and GATA3. Since GATA3 over-expression inhibits experimental Th17-mediated autoimmunity, we studied the contribution of GATA3 in vitamin D-mediated suppression of Th17 polarisation.
Methods Therefore CD4+ T cells were sorted from patients with early RA, naïve DBA-1 mice, DBA-1 mice immunised with collagen type II (CII) or naïve CD2-GATA3 transgenic mice and cultured under T helper cell polarising conditions with or without 1.25(OH)2D3, the active form of vitamin D.
Results 1.25(OH)2D3 inhibits Th17 polarisation in CD4+ cells from both non-immunised and CII-immunised mice, while up-regulating IL-4 and GATA3 expression. In these cultures, IL-4 inhibition partly reversed the vitamin D-mediated inhibition of Th17 polarisation. Moreover, GATA3 over-expression reduces Th17 differentiation to a lower level than 1.25(OH)2D3. Interestingly, combining GATA3 over-expression and 1.25(OH)2D3 treatment reduced IL-17A and RoRγ t expression even further. Furthermore, gene-expression analysis showed that NFAT-C2, which is involved in IL-17A production, was down-regulated by 1.25(OH)2D3. In addition, in T cells from patients with RA, 1.25(OH)2D3 inhibited Th17 cytokine and RORγ t expression and induced IL-4 and GATA3 expression.
Conclusions These data show that vitamin D-mediated regulation of Th17 polarisation occurs through GATA3-dependent mechanisms, including direct effects on RORγ t expression and IL-4-mediated inhibition of Th17 polarisation. Moreover, GATA3-independent mechanisms are involved that may include modulation of NFAT-C2 expression.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.