Abstract
BackgroundThe aim of this study was to investigate the protective effect of 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] on effector CD4+ T cells or on inflammatory cytokine-induced injury in human renal proximal tubular epithelial cells (HRPTEpiC).MethodsFirst, we investigated the effect of 1,25(OH)2D3 on CD4+ T cell proliferation. Second, we examined the effect of 1,25(OH)2D3 on inflammatory cytokine secretion or fibrosis in HRPTEpiC induced by inflammatory cytokines or activated CD4+ T cells using ELISA and real-time PCR. Lastly, we compared urine inflammatory-cytokine (IL-6, IL-8) or KIM-1 levels in kidney transplant recipients low serum 25-hydroxyvitamin D (25(OH)D) group (< 20 ng/mL) (n = 40) and normal 25(OH)D group (n = 50).ResultsPre-incubation with 1,25(OH)2D3 significantly reduced the percentages of Th1 and Th17 cells compared to that of Th0 condition (P < 0.05 for each). In contrast, 1,25(OH)2D3 increased the proportion of Th2 and Treg cells in a dose-dependent manner (P < 0.05 for each). Treatment of HRPTEpiC with inflammatory cytokines (TNF-α, IL-17, and TGF-β) or effector CD4+ T cells resulted in increased production of IL-6, IL-8, or KIM-1 from HRPTEpiC in a dose-dependent manner. However, treatment with 1,25(OH)2D3 significantly reduced the level of these cytokines (P < 0.05 for all). Western blot analysis demonstrated that the mTOR/STAT3/ERK pathway was downregulated by 1,25(OH)2D3 in HRPTEpiC. Furthermore, the concentrations of urine IL-6/creatinine (P < 0.05) and Kim-1/creatinine (P < 0.05) were higher in the low 25(OH)D group than in the normal 25(OH)D group in kidney transplant recipients.ConclusionThe results of this study suggests that vitamin D may have a significant role in the regulation of inflammation in allograft tissue in kidney transplant recipients.Trial registrationAll participants provided written informed consent in accordance with the Declaration of Helsinki. This study was approved by the Institutional Review Board of Seoul St. Mary’s Hospital (KC13TNMI0701).
Highlights
Recent studies have demonstrated the modulatory effects of vitamin D on various immune cells [1, 2]
1,25(OH)2D3 increased the proportion of T helper type 2 (Th2) and T regulatory (Treg) cells in a dose-dependent manner (P < 0.05 for each)
Treatment of HRPTEpiC with inflammatory cytokines (TNF-α, IL-17, and TGF-β) or effector CD4+ T cells resulted in increased production of IL-6, IL-8, or Kidney Injury Molecule-1 (KIM-1) from HRPTEpiC in a dose-dependent manner
Summary
Recent studies have demonstrated the modulatory effects of vitamin D on various immune cells [1, 2]. [10, 11] In kidney transplantation, 25(OH)D insufficiency was associated with high incidence of acute rejection or the development of urinary tract infection. This may be owing to the modulatory effect of vitamin D on immune cells. [3,4,5,6,7] For example, the effect of 1,25(OH)2D3 on allograft tissue, which is the target of alloimmune effector CD4+ T cells or inflammatory cytokines in acute rejection, has not been fully investigated. The rejection process is the activation of alloimmune effector T cells, and the injury to allograft kidney tissues. The aim of this study was to investigate the protective effect of 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] on effector CD4+ T cells or on inflammatory cytokine-induced injury in human renal proximal tubular epithelial cells (HRPTEpiC)
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