Molecular Mechanisms Underlying 1,25(OH)2D3-Mediated Suppression of Th17 Cell Activity

Wendy Dankers^1,2, Jan Piet van Hamburg^2,3, Wida Razawy^1,2, Nadine Davelaar^1,2, Anne-Marie Mus^1,2, Patrick Asmawidjaja^1,2, Johannes van Leeuwen⁴, Edgar Colin⁵ and Erik Lubberts^1,2, ¹Rheumatology, Erasmus MC, University Medical Center, Rotterdam, Netherlands, ²Immunology, Erasmus MC, University Medical Center, Rotterdam, Netherlands, ³Rheumatology, Erasmus MC, Rotterdam, Netherlands, ⁴Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, Netherlands, ⁵Rheumatology, ZGT, Almelo, Netherlands

Meeting: 2014 ACR/ARHP Annual Meeting

Keywords: interleukins (IL) and rheumatoid arthritis (RA), T cells, Vitamin D

Session Information

Title: T cell Biology in Rheumatoid Arthritis and Other Arthritis

Session Type: Abstract Submissions (ACR)

Background/Purpose

Vitamin D has suppressive effects on autoimmune diseases, such as rheumatoid arthritis (RA). Within these diseases, Th17 cells play a crucial role in the processes underlying chronic inflammation. Currently, Th17 cells are of high interest in the development of novel therapeutics, such as the development of antibodies against IL-17A or specific small molecule inhibitors of RORγt, the Th17 cell associated transcription factor.

Previously we have shown that the active vitamin D metabolite 1,25(OH)₂D₃is capable of directly inhibiting the polarization and pathogenic activity of Th17 cells. However the molecular mechanisms underlying this modulation of Th17 cell activity by vitamin D are currently unclear.

Methods

Therefore CD4⁺CD45RO⁺ (memory) and CCR6⁺ memory T-helper cells were sorted from peripheral blood of patients with early RA and healthy volunteers. They were cultured under in the presence or absence of 1,25(OH)₂D₃. The expression of cytokines and transcription factors of interest was analyzed using microarray based gene expression profiling, flow cytometry, ELISA and/or RT-PCR.

Results

In the presence of 1,25(OH)₂D₃ the pro-inflammatory cytokines IL-17A, IL-17F and IL-22 were inhibited. Also the expression of Th17 signature genes like RORγt and IL-23R was reduced. On the other hand we find an increase in IL-4 and IL-10 expression.
Interestingly neutralization of IL-4 partly reversed the effect of 1,25(OH)₂D₃on the inhibition of IL-17A, IL22 and RORγt expression. In addition, the inhibition of IL-17F by 1,25(OH)₂D₃was almost completely absent when IL-4 was blocked.

In contrast to IL-4, IL-10 neutralization had limited effects in these cultures.

Because the effect of 1,25(OH)₂D₃ is only partially dependent on IL-4, we examined factors that could play a role independent of IL-4. Gene expression profiling revealed that two transcription factors that are known to play a role in Th17 differentiation, EOMES and IRF8, are up regulated by 1,25(OH)₂D₃. EOMES and IRF8 are direct regulators of RORγt expression. Blocking IL-4 does not affect this up regulation, indicating that EOMES and IRF8 might be important in the IL-4 independent regulating of Th17 polarization by 1,25(OH)₂D₃.

Conclusion

From these findings, we conclude that 1,25(OH)₂D₃ is a direct modulator of Th17 cell activity. This modulation is partly dependent on up regulation of IL-4. IL-4 independent mechanisms may include the down-regulation of RORγt expression via up regulation of IRF8 and EOMES.

Disclosure:

W. Dankers,
None;

J. P. van Hamburg,
None;

W. Razawy,
None;

N. Davelaar,
None;

A. M. Mus,
None;

P. Asmawidjaja,
None;

J. van Leeuwen,
None;

E. Colin,
None;

E. Lubberts,
None.

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