.1,25 - Dihydroxyvitamin D <sub> 3 </ Sub> Immunomodulatory Effects Associated With Rheumatoid Arthritis Study

1,25-dihydroxyvitamin D3(1,25(OH)2D3) can modulate immune responses by inhibiting growth and differentiation of dendritic cells and T cells. It remains unknown whether1,25(OH)2D3can also directly modulate memory T cell function, cytokines production, and RANKL/OPG pathway.We observed that patients with rheumatoid arthritis (RA) have decreased levels of1,25(OH)2D3and that the levels were lowest in those with increased disease activity score in28joints (DAS28), clinical disease activity index (CDAI), C-reactive protein (CRP), swelling joint counts (SJC) and tender joint counts (TJC) suggesting that the possible immunoregulatory role of Vitamin D in RA.To address this possibility, we examined the effects of1,25-dihydroxyvitamin D3on memory T cell responses.1,25(OH)2D3was found to inhibit ongoing proliferation of activated memory T cells and induce their apoptosis.1,25(OH)2D3inhibits memory T-lymphocyte proliferation particularly in Thl cells and Th17cells, which further shifts the memory T-cell response toward Th2and Treg dominance by peripheral blood mononuclear cells from treatment-naive patients with early RA. Our observations in vitro have demonstrated that1,25(OH)2D3inhibits the synthesis of Thl cytokines IFN-γ,Thl7cytokines IL-17,IL-22,IL-6,TNF-a, and up-regulates Th2cytokines IL-4.RA is a chronic inflammatory disease that causes irreversible joint damage and significant disability. However, the fundamental mechanisms underlying how inflammation and joint destruction in RA develop and are sustained chronically remain largely unknown. Here, we show that receptor activator of nuclear factor-KB ligand(RANKL)/osteoprotegerin (OPG) system is the major pathway of both chronic inflammation and joint destruction in RA. We found that1,25(OH)2D3inhibit RANKL expression directly or indirectly in patients with early RA. Moreover,1,25(OH)2D3had favorable effects on IFN-γ:IL-4, TNF-a:IL-4and IL-17:IL-4ratios. Thus, our data provide evidence that1,25(OH)2D3may contribute its bone-sparing effects in early RA patients by the modulation of the Th1/Th17and Th2cytokine balance.Our data indicate that1,25-dihydroxyvitamin D3may play an important role in the maintenance memory T cell, cytokines and RANKL/OPG pathway homeostasis, and that correction of Vitamin D deficiency may be useful in the treatment of T cell mediated autoimmune disorders and RA.