1,25-dihydroxyvitamin D3 down-modulates the production of proinflammatory cytokines and nitric oxide and enhances the phosphorylation of monocyte-expressed STAT6 at the recent-onset type 1 diabetes

Background: Type 1 diabetes (T1D) is associated with an imbalance between inflammation and repair. Recently, the biologically active form of vitamin D-3, i.e. 1,25(OH)(2)D-3, has been reported to have potent immunomodulatory effects on both innate and adaptive immune cells, as well as on the production of their specific cytokines. Methods: We examined the effect of 1,25(OH)(2)D-3 on the production of proinflammatory Th1/Th17 and anti-inflammatory Th2/Treg related cytokines, as well as on the phosphorylation of monocyte-expressed STAT4 and STAT6 at the recent-onset human T1D. Results: The levels of IFN-gamma, IL-17 and nitric oxide (NO) production were significantly increased in peripheral blood mononuclear cells (PBMCs) from patients with T1D compared to controls. Similarly, STAT4 tyrosine phosphorylation (p-STAT4,Tyr693) levels were significantly increased in monocytes from patients when compared to controls. Conversely, the levels of IL-4, IL-10 and p-STAT6 (Tyr641) were significantly decreased in type 1 diabetic patients than in controls. Treatment with 1,25(OH)(2)D-3 resulted in significant up-regulation of IL-4, IL-10, arginase activity, and p-STAT6 and, conversely, down-regulation of IFN-gamma, IL-17 and NO production levels, as well as p-STAT4. Additionally, 1,25(OH)(2)D-3 significantly enhanced Treg-to-Th17 ratio, and induced a significant decrease in Thl-to-Th2, NO production-to-arginase activity and p-STAT4-to-p-STAT6 ratios. Conclusions: Our study suggests that the biologically active form of vitamin D can reverse the activation of inflammatory pathways at the onset of T1D. Additionally, its immunomodulation properties may vary depending on the overall patterns of cytokines. From a therapeutic point of view, vitamin D may potentially be suggested as an immunological adjuvant and a potential anti-inflammatory agent in individuals at risk of T1D. (C) 2016 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.