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THU0048 1,25(OH)2D3 Inhibits Th17 Polarization and RORC Expression Through GATA3-Dependent and -Independent Mechanisms
  1. W. Dankers1,
  2. J. P. van Hamburg1,
  3. A.-M. M. Mus1,
  4. P. S. Asmawidjaja1,
  5. J. P. van Leeuwen2,
  6. R. W. Hendriks3,
  7. L. Boon4,
  8. E. M. Colin5,
  9. E. Lubberts1
  1. 1Rheumatology
  2. 2Internal Medicine
  3. 3Pulmonary Diseases, ERASMUS MC, Rotterdam
  4. 4Bioceros, Utrecht
  5. 5ZGT, Almelo, Netherlands


Background 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 Rorγt, vitamin D induces IL-4 and GATA3. Interestingly, GATA3 over-expression inhibits experimental Th17-mediated autoimmunity.

Objectives We studied the contribution of GATA3 in vitamin D-mediated suppression of Th17 polarization.

Methods CD4+ T cells were sorted from patients with early RA, naïve DBA-1 mice, DBA-1 mice immunized with collagen type II (CII) or naïve CD2-GATA3 transgenic mice and cultured under T helper cell polarizing conditions with or without 1,25(OH)2D3, the active form of vitamin D.

Results 1,25(OH)2D3 inhibits Th17 polarization in CD4+ cells from both non-immunized and CII-immunized mice, while up-regulating IL-4 and GATA3 expression. In these cultures, IL-4 inhibition partly reversed the vitamin D-mediated inhibition of Th17 polarization. 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 Rorγt 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 RORγt expression and induced IL-4 and GATA3 expression.

Conclusions 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 expression.

Disclosure of Interest None Declared

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