Background Rheumatoid Arthritis (RA) is an auto-immune disease characterized by over proliferation of synovial tissues and following joint destruction. TNF-like ligand 1A (TL1A) is a member of TNF receptor superfamily [1,2] and involved in the pathogenesis of autoimmune diseases by inducing apoptosis via intracellular death domain or promoting inflammation through the activation of NFκB by binding to its specific receptor death receptor 3 (DR3) [3,4]. Meanwhile, decoy receptor 3 (DcR3) competitively binds soluble TL1A in addition to Fas-ligand (FasL) and LIGHT and inhibits the signaling of TL1A via DR3. DcR3 overexpressed in rheumatoid synovial fibroblasts (RA-FLS) stimulated with inflammatory cytokines such as TNFα or IL-1β inhibits Fas-induced apoptosis . In contrast, DcR3 inhibited cell proliferation induced by inflammatory cytokines via membrane-bound TL1A expressed on RA-FLS . Therefore, TL1A-DcR3/DR3 signaling may be involved in the pathogenesis of RA by modulating apoptosis and proliferation of RA-FLS.
Objectives In this study, we investigated the genes expression profiles regulated by TL1A in RA-FLS by comprehensive genetic analysis using microarrays to elucidate the involvement of TL1A in the pathogenesis of RA.
Methods Microarray assay. Four individual lines of primary cultured RA-FLS were incubated with either 1.0 μg/ml recombinant human TL1A protein or phosphate buffered saline (PBS) diluted with serum-free Opti-MEM medium as non-stimulated control for 12 hours at 37°C with 5% CO2. Gene expressions were detected by microarray assay (Human Genome U133 Plus 2.0, GeneChip® 3' Expression Array, Affymetrix).
Results The experiments revealed the expression profiles of genes in RA-FLS regulated by TL1A. The profiles showed that 501 genes were upregulated and 402 genes were downregulated among the genes whose expression variations of the TL1A-stimulated samples were more than twice of controls,. The functions of the genes include such as cell adhesion, cell signaling, cell junction, regulation of cell proliferation, regulation of cell activation, regulation of cell activation, and ion transport.
Conclusions In this study, we first revealed the gene expression profiles in RA-FLS regulated by TL1A. Previous studies suggested that the concentrations of TL1A in the synovial fluid and the serum of patients with RA was much higher than that with osteoarthritis (OA) and that the concentrations of TL1A was correlated with the disease activity of RA, particularly in the RF-positive patients with RA [3,7]. We newly reported the microarray data analysis that revealed the genes of which expression in RA-FLS was regulated by DcR3 . Thus TL1A-DR3/DcR3 signaling is suggested the involvement in the pathogenesis of RA. Further study of the genes detected in the current study may provide insight into the pathogenesis and treatment of rheumatoid arthritis by TL1A-DR3/DcR3 signaling.
Migone TS, et al. Immunity 2002 Mar; 16; 479-92.
Bamias G, et al. Clin Immunol 2008 Nov; 129; 249-55.
Zhang J, et al. J Immunol 2009 Oct 15; 183; 5350-7.
Chinnaiyan AM, et al. Science 1996 Nov 8; 274; 990-2.
Hayashi S, et al. Arthritis Rheum 2007 Apr; 56; 1067-75.
Takahashi M, et al. Int J Mol Med 2011 Sep; 28; 423-7.
Cassatella MA, et al. J Immunol 2007 Jun 1; 178; 7325-33.
Fukuda K, et al. Int J Mol Med 2013 Oct; 32; 910-6.
Disclosure of Interest None declared