AB0090 DEATH RECEPTOR 3 REGULATES THE GENE EXPRESSIONS OF VARIOUS KEY MOLECULES IN RHEUMATOID SYNOVIAL FIBROBLASTS

Background:Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes hyperplasia of synovial tissue. Death receptor 3 (DR3) is a tumor necrosis factor receptor and binds to TL1A, a member of the TNF family. DR3 is involved in the mechanism of cell proliferation and apoptosis through NF-κB signaling. Suppression of DR3 in rheumatoid synovial fibroblasts (RA-FLS) is associated with hyperplasia of rheumatoid synovial tissue [1]. We previously revealed the expression profiles regulated by TL1A, suggesting that TL1A might affect the pathogenesis of RA, including proliferation, regulation of B cells and T cells, inflammation, and cytokine processing [2].Objectives:In this study, we investigated the gene expression profiles regulated by DR3 in RA-FLS to reveal how DR3 is involved in the pathogenesis of RA.Methods:RA-FLS were from patients with RA. Four individual lines of primary cultured RA-FLS were incubated either with 1000 ng/ml of human DR3-Fc protein or 1000ng/ml of human IgG1 as a control for 12h. Gene expressions were detected by microarray assay.Results:Microarray data analysis revealed that DR3 up-regulated or down-regulated the expression of various genes in RA-FLS (Figure). The function of regulated genes included protein-L-isoaspartate (D-aspartate) O-methyltransferase activity, carboxyl-O-methyltransferase activity, protein carboxyl O-methyltransferase activity, regulation of cilium assembly, O-methyltransferase activity, regulation of plasma membrane bounded cell projection assembly, regulation of cell projection assembly, regulation of organelle assembly, protein methyltransferase activity, and S-adenosylmethionine-dependent methyltransferase activity. The most up-regulated 2 genes by DR3 were KIAA1109 (KIAA1109), and adhesion G protein-coupled receptor A3 (ADGRA3). The most down-regulated 2 genes by DR3 were RNA exonuclease 2 (REXO2), and family with sequence similarity 120A (FAM120A).Conclusion:In this study, we first revealed the expression profiles of genes regulated by DR3 in RA-FLS. KIAA1109/TENR/IL2/IL21 gene is strongly associated with RA in European descent populations [3]. ADGRA3 is a member of G protein-coupled receptors (GPCRs). GPCRs associates with the regulation of cytoskeletal organization, the cell adhesion and migration, cell proliferation and apoptosis, and cell differentiation [4]. Loss of REXO2 affects cell growth and morphology [5], and REXO2 was identified as a target gene for inflammatory bowel disease-associated variants [6]. FAM120A regulates activity of Src kinase to protect cells from oxidative stress-induced apoptosis [7]. DR3 regulates the gene expressions of various key molecules in RA-FLS and may affect the pathogenesis of RA by regulating gene expression of RA-FLS.References:[1]Takami N. et al., Arthritis Rheuma. 2006;54:779-787.[2]Fukuda K. et al., Biomed Rep. 2019;1:1-5.[3]Teixeira VH. et al., Arthritis Research & Therapy. 2009;11:R45.[4]Hamann J. et al., Pharmacol Rev. 2015;67:338-367.[5]Bruni F, et al., PLoS One. 2013;8:e64670.[6]Hulur I, et al., BMC Genomics. 2015;16:138.[7]Tanaka M. et al., Mol Cell Biol. 2009;29:402-413.Disclosure of Interests:None declared

Expression of death receptor 3 (DR3) on peripheral blood mononuclear cells of patients with psoriasis vulgaris

BackgroundA series of previous reports indicated that tumour necrosis factor-like ligand 1A (TL1A) and its receptor death receptor 3 (DR3) are involved in the pathogenesis of psoriasis vulgaris (PV), which is a common chronic skin disease accompanied by a number of comorbidities, although their exact roles remain unclear. Our previous studies demonstrated that serum TL1A levels were substantially elevated in patients with PV, but the detection of DR3 expression in peripheral blood mononuclear cells (PBMCs) of patients with PV had not been reported. Therefore, we detected DR3 expression on CD4+, CD8+, CD14+ and CD19+ PBMCs of patients with PV, atopic dermatitis (AD) and healthy volunteers.MethodsBlood samples were collected from participants with PV before and after treatment. Then, PBMCs from patients with PV were isolated. The Psoriasis Area Severity Index (PASI) was used to assess severity in patients with PV. The DR3 on CD4+, CD8+, CD14+ and CD19+ PBMCs were detected by flow cytometry analysis. Pearson’s correlation analysis was then used to investigate the relationship between DR3 expression and PASI scores in patients with PV.ResultsComparing with the healthy volunteers and patients with AD, the percentage of DR3-expressing on CD8+ and CD14+ PBMCs in patients with PV was elevated, but the percentage of DR3-expressing on CD8+ and CD14+ cells decreased after anti-inflammatory treatment, which was correlated with PASI scores.ConclusionsTaken together, these findings suggest that DR3 may play a key role in the pathogenesis of PV.