The Role Of Indoleamine 2,3-Dioxygenase 1 In The Pathogenesis Of Vogt-koyanagi-harada Disease

Background:Previous studies have pointed out that indoleamine2,3-dioxygenase 1(IDO1),the rate-limiting enzyme initiating tryptophan metabolism,plays a role in the regulation of the immune system.This project was designed to investigate the potential role of IDO1 in monocyte-derived dendritic cells(moDCs)obtained from active Vogt-Koyanagi-Harada disease(VKH)patients to further understand the pathogenesis of VKH syndrome.Methods:The IDO1 mRNA expression and enzyme activity(determined by the Kyn/Trp ratio)in VKH patients and normal volunteers were assessed by quantitative RT-PCR and LC-MS analysis.An effective inhibitor named 1-methyl-L-tryptophan(1-MT)was used to suppress IDO1activity in DCs in vitro.Flow cytometry was performed to investigate the effect of 1-MT on the phosphorylation of the mitogen-activated protein kinase(MAPK)pathway,the maturation markers of DCs,and the differentiation of CD4~+T cells.The cytokine profiles generated by DCs were quantified by ELISA.Proliferation of CD4~+T cells was measured by the CCK8 assay.Results:The mRNA expression of IDO1 in DCs and its enzyme activity from active VKH patients were increased when compared with inactive patients and normal volunteers.Inhibition of IDO1 with 1-MT decreased the expression of the DC marker CD86.Downregulation of IDO1 in DCs also led to the reduction of regulatory T(Treg)cells and an increased CD4~+T cell proliferation.Treatment with 1-MT did not affect the cytokines production and the MAPK pathway phosphorylation in DCs.Conclusions:Our study suggests that activated IDO1 may play an important role in the pathogenesis of VKH disease by promoting DC maturity and Treg cell differentiation as well as inhibiting CD4~+T cell proliferation.