A4.1 1.25(OH)2D3Modulates Gene Expression Involved in Phenotype Stability and Migration of Th17 Cells from Patients with Rheumatoid Arthritis

Background and Objectives 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 chronic inflammation. Recently, we have found that the active vitamin D compound, 1.25(OH) 2 D 3 , has direct suppressive effects on both human and mouse Th17 cytokine expression and activity. Using gene-expression profiling, we aim to identify molecular targets of 1.25(OH) 2 D 3 signalling underlying this suppressive action of 1.25(OH) 2 D 3 in Th17 cells. Methods Primary Th17 cells were sorted from peripheral blood of treatment naive patients with early RA and cultured with or without 1.25(OH) 2 D 3 . 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) 2 D 3 , 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) 2 D 3 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, RORγ t, 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) 2 D 3 . Conclusions From these findings, we concluded that 1.25(OH) 2 D 3 modulates the expression of genes involved in cytokine production, proliferation, and migration of Th17 cells. These data indicate that 1.25(OH) 2 D 3 not only suppresses Th17 cell activity but also regulates Th17 phenotype stability and migration of these cells to sites of tissue inflammation in RA.