Soluble TNF-Like Cytokine (TL1A) Production by Immune Complexes Stimulated Monocytes in Rheumatoid Arthritis

Abstract

TNF-like cytokine (TL1A) is a newly identified member of the TNF superfamily of ligands that is important for T cell costimulation and Th1 polarization. However, despite increasing information about its functions, very little is known about expression of TL1A in normal or pathological states. In this study, we report that mononuclear phagocytes appear to be a major source of TL1A in rheumatoid arthritis (RA), as revealed by their strong TL1A expression in either synovial fluids or synovial tissue of rheumatoid factor (RF)-seropositive RA patients, but not RF−/RA patients. Accordingly, in vitro experiments revealed that human monocytes express and release significant amounts of soluble TL1A when stimulated with insoluble immune complexes (IC), polyethylene glycol precipitates from the serum of RF+/RA patients, or with insoluble ICs purified from RA synovial fluids. Monocyte-derived soluble TL1A was biologically active as determined by its capacity to induce apoptosis of the human erythroleukemic cell line TF-1, as well as to cooperate with IL-12 and IL-18 in inducing the production of IFN-γ by CD4+ T cells. Because RA is a chronic inflammatory disease with autoimmune etiology, in which ICs, autoantibodies (including RF), and various cytokines contribute to its pathology, our data suggest that TL1A could be involved in its pathogenesis and contribute to the severity of RA disease that is typical of RF+/RA patients.

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]. …”

Directed evolution of a soluble human DR3 receptor for the inhibition of TL1A induced cytokine secretion

“…Binding of TL1A to DR3 triggers proliferative signals, most likely via the activation of NF-κB-associated pathways [4]. It was shown that TL1A increases IFN-γ production by acting in synergy with IL-12 and IL-18 and can thus bias the immune response towards a type 1 T helper cell (T H 1)-like response [6,7]. It was first shown that TL1A is expressed by endothelial cells, with such expression being significantly enhanced by treatment with TNF-α or IL-1 [8].…”