Session Title: T cell Biology in Rheumatoid Arthritis and Other Arthritis
Session Type: Abstract Submissions (ACR)
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.
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.
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)2D3 on the inhibition of IL-17A, IL22 and RORγt expression. In addition, the inhibition of IL-17F by 1,25(OH)2D3 was 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.
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.
J. P. van Hamburg,
A. M. Mus,
J. van Leeuwen,
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