1,25(OH)2D3 Modulates the Migration Pattern of Th17 Cells From Patients with Rheumatoid Arthritis

Wendy Dankers¹, Jan Piet van Hamburg², Patrick S. Asmawidjaja¹, Nadine Davelaar¹, Hoyan Wen³, Anne-Marie Mus¹, Edgar Colin², Johannes van Leeuwen⁴, Johanna M.W. Hazes⁵ and Erik Lubberts¹, ¹Rheumatology, Erasmus MC, University Medical Center, Rotterdam, Netherlands, ²Rheumatology, Erasmus MC, Rotterdam, Netherlands, ³Rheumatology and Immunology, Erasmus MC, University Medical Center, Rotterdam, Netherlands, ⁴Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, Netherlands, ⁵Rheumatology, Erasmus University Medical Center, Rotterdam, Netherlands

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: chemokines, cytokines, rheumatoid arthritis (RA) and vitamins, T cells

Session Information

Title: T-cell Biology and Targets in Autoimmune Disease

Session Type: Abstract Submissions (ACR)

Background/Purpose:

Vitamin D has suppressive effects on autoimmune diseases, such as rheumatoid arthritis (RA). Within these diseases, T-helper-17 (Th17) cells have been implicated to play a crucial role in the development and progression of persistent inflammation. Recently, we have shown that Th17 cells are able to activate synovial fibroblasts of patients with RA (RASF) resulting in a pro-inflammatory feedback loop. This leads to increased production of pro-inflammatory cytokines and tissue-degrading enzymes. We have found that the active vitamin D compound, 1,25(OH)₂D₃, has direct suppressive effects on Th17 cells from patients with early RA. In addition 1,25(OH)₂D₃is capable of inhibiting the pro-inflammatory feedback loop between Th17 cells and RASF. The objective of this study is to identify molecular targets of 1,25(OH)₂D₃ signaling underlying this suppressive action of 1,25(OH)₂D₃ in Th17 cells.

Methods:

Primary Th17 cells were sorted from peripheral blood of treatment naïve patients with early RA. They were cultured with or without 1,25(OH)₂D₃ alone or together with RASF. From these cultures gene-expression profiles were generated. Expression of genes of interest was confirmed by Q-PCR and/or specific ELISA.

Results:

In the presence of 1,25(OH)₂D₃, protein expression of Th17 associated cytokines IL-17A and IL-22 was inhibited, while in contrast the anti-inflammatory cytokine IL-10 was induced. These findings were supported by the gene-expression profiles from these cultures. Furthermore, 1,25(OH)₂D₃ inhibited transcription of the cytokine receptors IL-23R and IL-7R, which are involved in Th17 survival and proliferation. Chemokines CCL20 and CXCL10 were down-regulated and chemokine receptors CCR2, CXCR6, CXCR3 and CCR10 were up-regulated. Importantly, Rorγt, which is critically involved in Th17 differentiation and function and the cell-size regulator and oncogene c-Myc were down-regulated by 1,25(OH)₂D₃.

Conclusion:

From these findings, we concluded that 1,25(OH)₂D₃ modulates the expression of genes involved in cytokine production, proliferation, and migration of Th17 cells. These data indicate that 1,25(OH)₂D₃ not only suppresses Th17 cell activity but also regulates Th17 phenotype stability and migration of these cells to sites of tissue inflammation in RA.

Disclosure:

W. Dankers,
None;

J. P. van Hamburg,
None;

P. S. Asmawidjaja,
None;

N. Davelaar,
None;

H. Wen,
None;

A. M. Mus,
None;

E. Colin,
None;

J. van Leeuwen,
None;

J. M. W. Hazes,
None;

E. Lubberts,
None.

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