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Peizeng Yang, Chaokui Wang, Zi Ye, Aize Kijlstra; Activation of the aryl hydrocarbon receptor(AhR) inhibits Th1 and Th17 cell immune response in Behcet’s disease. Invest. Ophthalmol. Vis. Sci. 2013;54(15):5374.
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© ARVO (1962-2015); The Authors (2016-present)
Recent studies show that AhR is involved in immune response. AhR exert its role via interaction with its ligands, such as 6-formylindolo[3,2-b]carbazole (FICZ), and 2-(1’Hindole-3’-carbonyl)-thiazole-4- carboxylic acid methyl ester (ITE). In this study, we investigated the role of AhR activation by its endogenous ligands in the aberrant immune response of Behcet’s disease and the possible immunologic mechanisms involved.
AhR mRNA and protein expression in peripheral blood mononuclear cells (PBMCs) from active BD patients, inactive BD patients and normal controls was examined using RT-PCR and flow cytometry. The effect of FICZ and ITE on PBMCs, CD4+ T cells, DCs, retinal pigment epithelium(RPE) was detected by ELISA and flow cytometry. Flow cytometry was performed to study the mechanisms involved in the effect of FICZ and ITE on CD4+ T cells and DCs.
The expression of AhR was significantly decreased in active BD patients as compared to inactive BD patients and normal controls. Both FICZ and ITE inhibited Th1 and Th17 polarization, and induced the expression of IL-22 by PBMCs and CD4+ T cells. The effect of FICZ and ITE on CD4+ T cells was associated with a decreased expression of RORC, IL-17, IL-23R, CCR6, decreased phosphorylation of STAT3, and increased phosphorylation of STAT5. FICZ- or ITE-treated DCs showed a decreased expression of co-stimulatory molecules including HLA-DR, CD80 and CD86, lower production of pro-inflammatory cytokines such as IL-1β, IL-6, IL-23 and TNF-α, and higher production of IL-10, in association with lower stimulation on Th1 and Th17 cell polarization. The inhibition of both ligands on DCs was mediated via suppressing the phosphorylation of P38 and JNK. AhR was also found to be expressed by RPE. Both FICZ and ITE could inhibit the IL-8 and IL-6 secretion by the RPE stimulated with TNF-α or LPS.
The present study suggests that a decreased AhR expression is associated with disease activity in BD patients. The activation of AhR either by FICZ or ITE showed a negative regulation role in the pathogenesis of BD as evidenced by its inhibition on Th1 and Th17 cell polarization, the maturation, differentiation and function of DCs, as well as the inflammatory cytokine secretion by RPE.
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