Role of TL1A in Inflammatory Autoimmune Diseases: A Comprehensive Review

Abstract

TL1A, also called TNFSF15, is a member of tumor necrosis factor family. It is expressed in different immune cell, such as monocyte, macrophage, dendritic cell, T cell and non-immune cell, for example, synovial fibroblast, endothelial cell. TL1A competitively binds to death receptor 3 or decoy receptor 3, providing stimulatory signal for downstream signaling pathways, and then regulates proliferation, activation, apoptosis of and cytokine, chemokine production in effector cells. Recent findings showed that TL1A was abnormally expressed in autoimmune diseases, including rheumatoid arthritis, inflammatory bowel disease, psoriasis, primary biliary cirrhosis, systemic lupus erythematosus and ankylosing spondylitis. In vivo and in vitro studies further demonstrated that TL1A was involved in development and pathogenesis of these diseases. In this study, we comprehensively discussed the complex immunological function of TL1A and focused on recent findings of the pleiotropic activity conducted by TL1A in inflammatory autoimmune disease. Finish of the study will provide new ideas for developing therapeutic strategies for these diseases by targeting TL1A.

Keywords: DR3; TL1A; TNFSF15; immune response; inflammatory autoimmune disease.

Figure 1

Signal transduction initiated by TL1A/DR3. TL1A binds to the receptor DR3 and activates the TRADD pathway. The complex exerts pro-inflammatory effects by regulating downstream pathways, such as TRAF2, RIP1, PI3K, MAPKs, NF-κB, and then regulates cytokine, chemokine secretion. TL1A/DR3 is involved in promoting apoptosis and necroptotic cell death through FADD, RIP3, Caspase-8/-3/-7 pathways. NF-κB can activate c-IAP protein, which can negatively regulate apoptosis. TRADD, TNFR-associated death domain protein; TRAF2, TNFR-associated factor 2; RIP1, receptor-interacting protein 1; PI3K, phosphatidylinositol 3-kinase; MAPKs, mitogen-activated protein kinases; NF-κB, nuclear factor kappa B; FADD, fas-associated death domain; RIP3, receptor-interacting protein 3; c-IAP, cellular inhibitor of apoptosis proteins.

Figure 2

Role of TL1A in immune cells. Monocyte (Mo) and macrophage, endothelial cells, dendritic cell, chondrocyte, and synovial fibroblast produce TL1A, which regulates production of inflammatory cytokines and chemokines in different immune cells, including ILC, T cells and NK cells. ILC, innate lymphoid cells; NK cell, natural killer cell; Th, helper T cell; IL-1β, interleukin-1β; TNF-α, tumor necrosis factor-α; TGF-β, transforming growth factor-β; GM-CSF, granulocyte­macrophage colony stimulating factor; IFN-γ, interferon−γ.