Elucidation of the expression and clinical significance of tripartite motif-containing proteins in Behcet``s disease = Elucidation of the expression and clinical significance of tripartite motif-containing proteins in Behcet``s disease

다국어 초록 (Multilingual Abstract)

Background: Behcet’s disease (BD) is a chronic, multisystem vasculitis and autoinflammatory disorder, characterized by oral ulcers, genital ulcers, various inflammatory skin lesions, and uveitis. The exact cause of BD is still not known, many study suggest that this disease triggered by environmental factor including infectious agents such as herpes simplex virus (HSV) and streptococcus sanguinis. Tripartite motif containing 21 (TRIM21), an E3 ligase protein, regulates the production of cytokine by ubiquitination of transcriptional factors such as interferon regulatory factor (IRF) family and NF-kB. Moreover TRIM21 can present antiviral properties, mediating antiviral defense mechanisms to DNA/RNA viruses. Objective: The purpose of this study was to elucidate TRIM21 proteins expression in monocyte of BD patient, and to identify the role of TRIM21 on immune dysregulation in BD. Methods: Monocytes and T cells were isolated from peripheral blood using Ficoll-Hypaque density-gradient centrifugation and relevant immunomagnetic negative selection method. Protein levels were measured using western blot, ELISA, and flow cytometry. Co-cultures between monocyte and responder T cells (1:1 to 1:2 ratio) were maintained in media for 7~14 days. Knock-down of TRIM21 was performed using siRNA technique on THP-1 or freshly isolated monocytes. Results: TRIM21 expression was increased in peripheral blood monocytes from BD patients compared to healthy control. The expression of IRF8, a representative ubiquitination target of TRIM21, was also decreased in BD monocyte. BD monocyte promoted secretion of pro- inflammatory cytokines including Th17 promoting cytokine such as IL-6, IL-1β and IL-23 following NF-kB activation. BD monocytes promoted Th17 polarization after co-culture with responder T cells from healthy donors, and IL-17A production from these co-cultured T cells was also increased. Known-down of TRIM21 in monocyte using siRNA prevents NF-kB activation and decreased Th1 and Th17 polarization of responder T cell in co-culture system. Conclusion: From our results suggest that BD monocytes facilitate Th/1Th17 differentiation of naive T cells and TRIM21 may regulate the secretion of pro-inflammatory cytokine from monocytes.