Abstract
Aberrant methylation change of IRF8 confers risk to various tumors, and abnormal expression of IRF8 is involved in many autoimmune diseases, including ocular Behcet’s disease. However, whether the methylation change of IRF8 is associated with Vogt-Koyanagi-Harada (VKH) disease remains unknown. In the present study, we found a decreased IRF8 mRNA expression in association with a higher methylation level in monocyte-derived dendritic cells (DCs) from active VKH patients compared with the normal and inactive subjects. DCs incubated with cyclosporin a (CsA) or dexamethasone (DEX) showed a lower methylation and higher mRNA expression of IRF8 in active VKH patients. A demethylation reagent, 5-Aza-2′-deoxycytidine (DAC) showed a notable demethylation effect as evidenced by increasing the mRNA expression and reducing the methylation level of IRF8. It also suppressed the Th1 and Th17 responses through down-regulating the expression of co-stimulatory molecules (CD86, CD80, CD40), and reducing the production of pro-inflammatory cytokines (IL-6, IL-1β, IL-23, IL-12) produced by DCs. These findings shows that hypermethylation of IRF8 in DCs confers risk to VKH disease. Demethylation of IRF8 may offer a novel therapeutic strategy protect against VKH disease.
Highlights
Interferon regulatory factor 8 (IRF8) belongs to the IRF transcription factor family[11], that modulates the immune response and other important physiologic processes, including cell growth and oncogenesis[12]
This study shows that the IRF8 mRNA level in dendritic cells (DCs) acquired from active VKH subjects is lower compared to normal controls, whereas the methylation of the IRF8 promoter region is higher
Testing DCs from patients that had responded to treatment and who had entered an inactive phase of the disease showed a down-regulated methylation level and increased mRNA expression of IRF8 compared to active VKH patients
Summary
Interferon regulatory factor 8 (IRF8) belongs to the IRF transcription factor family[11], that modulates the immune response and other important physiologic processes, including cell growth and oncogenesis[12]. Studies in the experimental autoimmune uveitis model in mice showed that intraocular inflammation is exacerbated in mice with a targeted IRF8 deletion in their T cells whereby disease enhancement correlated with Th17 cell expansion and a decrease in T regulatory cells[22]. These studies prompted us to further investigate the possible role of IRF8 in clinical uveitis whereby we decided to investigate whether the epigenetic control of IRF8 function might be associated with disease development. The results show that hypermethylation of IRF8 confers risk to VKH disease
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