DcR3-TL1A signalling inhibits cytokine-induced proliferation of rheumatoid synovial fibroblasts

Abstract

Abstract. decoy receptor 3 (dcr3), a member of the tumour necrosis factor receptor (tnfr) superfamily, lacks the transmembrane domain of conventional tnfrs in order to be a secreted protein. dcr3 competitively binds and inhibits members of the tnf family, including fas ligand (fasl), liGHt and tl1a. We previously reported that tnfα-induced dcr3 overexpression in rheumatoid synovial fibroblasts (ra-flS) protects the cells from fas-induced apoptosis and that dcr3 induces Vla-4 expression in tHP-1 macrophages to inhibit cycloheximide-induced apoptosis. meanwhile, recent studies have suggested that dcr3 acting as a ligand directly induces the differentiation of macrophages to osteoclasts. therefore, in the present study, we analyzed the direct effects of dcr3 as a ligand in ra-flS. the experiments showed that dcr3 binds to tl1a expressed in ra-flS resulting in the negative regulation of cell proliferation induced by inflammatory cytokines. DcR3-TL1A signalling may be involved in the pathogenesis of rheumatoid arthritis (ra). IntroductionRheumatoid arthritis (RA) is an inflammatory joint disease characterized by hyperplasia of the synovial tissue and formation of pannus, which grow invasively into the cartilage, causing cartilage and bone destruction. analyses of hyperplastic synovial tissues of patients with ra have revealed a number of features of transformed long-living cells, such as the presence of somatic mutations, expression of oncogenes, and resistance to apoptosis (1-3).We recently reported that the decoy receptor 3 (dcr3)/ TR6/M68/TNFRSF6b is expressed in rheumatoid fibroblastlike synoviocytes (ra-flS), and that dcr3 expression induced in ra-flS by tnfα protected the cells from fas-induced apoptosis (4). dcr3, a member of the tumour necrosis factor receptor (tnfr) superfamily, lacks the transmembrane domain of conventional tnfrs to be a secreted protein (5). dcr3 is typically overexpressed in tumour cells, including lung and colon cancers (5), gliomas, gastrointestinal tract tumours (6) and virus-associated leukaemia (7). in addition, dcr3 is expressed in some normal tissues, including the colon, stomach, spleen, lymph nodes, spinal cord, pancreas and lungs (5,6). However, dcr3 is not expressed in human fibroblast NIH3T3 cells (8). DcR3 has three ligands, i.e., the fas ligand (fasl), liGHt and tl1a, all members of the tnf superfamily (9). Overexpression of DcR3 may benefit tumours by helping them to avoid the cytotoxic and regulatory effects of fasl (5), liGHt (10) and tl1a (11). We suggest that dcr3 is one of the key molecules that regulate the proliferation of ra-flS (4). recent studies have suggested that dcr3 directly induces osteoclast formation from monocytes (12), and that dcr3 triggers enhanced adhesion of monocytes via reverse signalling (13). However, it remains unclear whether dcr3 directly affects ra-flS proliferation. further, the molecules interacting with dcr3 for reverse signalling remain unknown. meanwhile, it has been reported that the dcr3 ligand proteins, fasl, liGHt and tl1a, are all e...

The Tumor Necrosis Factor Superfamily Members TWEAK, TNFSF15 and Fibroblast Growth Factor-Inducible Protein 14 Are Upregulated in Proliferative Diabetic Retinopathy

“…In addition, TNFSF15 expression in PDR epiretinal membranes correlated with the activity of angiogenesis. Our results in PDR are in agreement with previous studies that demonstrated TNFSF15 expression by synovial fibroblasts and mononuclear phagocytes in synovial tissue of rheumatoid arthritis patients [36,37], by endothelial cells and macrophage/foam cells in atherosclerotic plaques [39], by mononuclear and neutrophil infiltration, perivascular spindle-like cells, and endothelial cells in psoriatic skin lesions [38], and by macrophages and CD4+ and CD8+ lymphocytes in intestinal tissue specimens from patients with Crohn's disease [30]. …”

“…Further studies have shown that it is also secreted by monocytes/macrophages, dendritic cells, CD4+ and CD8+ T cells, and synovial fibroblasts [30,36,37,38,39]. Using immunohistochemistry, we demonstrated for the first time that the TNFSF15 protein was specifically localized in vascular endothelial cells, mononuclear cells and myofibroblasts in epiretinal membranes from patients with PDR.…”

“…These mediators are implicated in the progression of PDR. Recent studies have clearly shown that TNFSF15 is upregulated and possibly implicated in the pathogenesis of several chronic inflammatory conditions including inflammatory bowel disease [29,30,31,32], rheumatoid arthritis [33,34,35,36,37], psoriatic skin lesions [38], and atherosclerosis [39]. The serum and synovial fluid levels of TNFSF15 are elevated in patients with rheumatoid arthritis [33,34,35], and TNFSF15 aggravated collagen-induced arthritis in mice [35].…”

“…In addition, TNFSF15 helps to modulate the immune system by stimulating T cell activation, T helper 1 cytokine production and dendritic cell maturation [15,16]. Recent studies have clearly shown that TNFSF15 is upregulated and possibly implicated in the pathogenesis of several chronic inflammatory conditions [29,30,31,32,33,34,35,36,37,38,39]. …”

Downregulation of DcR3 sensitizes hepatocellular carcinoma cells to TRAIL-induced apoptosis

“…DcR3, a member of the soluble TNF receptor (TNFR) superfamily, sharing a similar sequence with OPG, TNF2, and Fas, can competitively bind to FasL, TL1A, and LIGHT, inhibit apoptosis, modulate immune function, and induce angiogenesis 17–19. DcR3 has been found to be highly expressed in many malignant tumors 20–23.…”