Background In many human autoimmune diseases, including rheumatoid arthritis (RA), vitamin D is associated with disease suppression. Furthermore, experimental collagen-induced arthritis (CIA) is prevented by 1,25(OH)2D3 supplementation, the active form of vitamin D. Since high doses of 1,25(OH)2D3 in humans can cause serious side effects, understanding the mechanism behind the suppression may lead to new therapeutic targets. Although currently this mechanism is not known, it is hypothesised that Th17 cells play an important role in the immunomodulatory effect of vitamin D. Here we study the effect of 1,25(OH)2D3 on the differentiation of Th17 cells and the underlying mechanism in the context of the autoimmune-mediated CIA model.
Materials and methods DBA/1 mice were immunised with type II collagen (CII) in complete Freund’s adjuvant. 10 days after immunisation the mice were sacrificed and spleens were harvested. Total CD4+, naïve CD4+ or effector CD4+ T cells were isolated and cultured for 3–7 days under Th17 polarising conditions with or without 1,25(OH)2D3.
Results 1,25(OH)2D3 inhibits Th17 differentiation in total CD4+ T cells in CII-immunised mice. Interestingly, 1,25(OH)2D3 induces IL-4 and IL-10 in these cells. Therefore we investigated whether the effect of 1,25(OH)2D3 on Th17 differentiation was dependent on IL-4 or IL-10. In both naïve and effector CD4+ T cells from CII-immunised mice, 1,25(OH)2D3 inhibited Th17 differentiation as demonstrated by decreased IL-17A, IL-17F and IL-22. Blocking IL-10 did not prevent this effect in either subsets. However, in the effector cells, but not the naïve cells, blocking IL-4 partially reduced the effect of 1,25(OH)2D3 on Th17 differentiation.
Conclusions 1,25(OH)2D3 similarly inhibits Th17 differentiation of naïve and effector CD4+ T cells from CII-immunised mice. However, only the inhibition in effector cells, not in naïve cells, is partially dependent on IL-4. These data show that 1,25(OH)2D3utilises different pathways to inhibit Th17 differentiation, depending on the maturation stage of the CD4+ T cell.
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