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. It has been found that TL1A is aberrantly expressed in autoimmune diseases and is involved in autoimmune diseases such as rheumatoid arthritis, psoriasis, and inflammatory bowel disease, etc. TL1A plays an important role in inflammatory responses, etc., due to its unique mechanism of action. Currently, TL1A has become a new target for diseases such as ulcerative colitis and Crohn's disease.

TL1A/DR3 Signaling Pathway

DR3 is a type 1 membrane protein and contains four cysteine residues, two potential N-linked glycosylation sites, a transmembrane domain and a cytoplasmic domain with a death domain (DD). Two different signaling pathways could be triggered by sTL1A/DR3 interaction, causing inflammation and apoptosis, respectively.

First, death domain of DR3 combined with adapter protein TNFR-associated death domain protein (TRADD) in the cytoplasm, and then recruited TNFR-associated factor 2 (TRAF2) and receptor-interacting protein 1 (RIP1). These complexes activated MAPKs (ERK, p38, and JNK), NF-κB, and the effector kinases PI3K signaling. Finally, the activated signalings regulated expression of pro-inflammatory genes and participated in occurrence of immune related diseases.

TRADD binds to Fas-associated death domain (FADD) and RIP3, and then activates cysteinyl aspartate specific proteinase-8 (caspase-8) to form complexes, which further activate downstream caspase pathways (for example, caspase-3 and -7) and induce apoptotic cell death. Combination of FADD, RIP3, RIP1 and the downstream effector molecule mixed lineage kinase domain-like protein (MLKL) forms a cytosolic “necrosome” complex after phosphorylation when caspase-8 activity is blocked. Then, MLKL oligomerizes to the cell membrane, and causes necroptotic cell death, a form of cell death with intense inflammation. More evidence suggests that sTL1A attachment to DR3 preferentially induces pro-inflammatory pathways in lymphocytes rather than apoptosis.

Fig. 1 Signal transduction initiated by TL1A/DR3.

TL1A binds to the receptor DR3 and activates the TRADD pathway. This complex exerts pro-inflammatory effects by regulating downstream pathways such as TRAF2, RIP1, PI3K, MAPKs, NF-κB, etc., which in turn regulates cytokine and chemokine secretion.TL1A/DR3 is involved in the promotion of apoptosis and necroptosis through the FADD, RIP3, and caspase-8/-3/-7 pathways.NF-κB activates the c- IAP protein, thereby negatively regulating apoptosis.TL1A binds to receptor DR3 and activates the TRADD pathway. NF-κB can activate c- IAP protein, thereby negatively regulating apoptosis. TL1A stimulates the TH1 and TH17 pathways, which are associated with the site and severity of intestinal inflammation and fibrosis. In addition, TL1A activates fibroblasts, which are a major source of fibrosis. Thus, TL1A is an important factor regulating mucosal immunity and fibrosis.

Inflammatory Bowel Disease (IBD)

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a group of chronic inflammatory bowel diseases whose pathogenesis is related to susceptibility genes, immune system dysregulation, and environmental factors.

TNF is considered a pro-inflammatory cytokine in the pathogenesis of IBD, stimulating responses during the acute phase, promoting the secretion of IL-1 and IL-6, and increasing the expression of adhesion molecules. TNF-α was found to be significantly elevated in blood, epithelial tissue, and feces of patients with active IBD, and its level correlated with clinical disease activity in CD patients. Blocking TNF-α signaling by anti-TNF-α monoclonal antibodies has become an important therapeutic approach for patients with moderate-to-severe refractory IBD. TL1A, a member of the TNF family, has also been found to be a key mediator of intestinal inflammation, and levels are also elevated in patients with IBD. TL1A exerts its function primarily through binding to death receptor 3 (DR3). TL1A also synergistically promotes the production of IL-4, IL-12, and IL-23, and increases the expression of DR3 through Th1, Th2, and Th17 cells in order to promote inflammation. Thus, targeting TL1A has shown IBD therapeutic potential in preclinical and clinical studies.

TNFSF15-Related Products Used to Fuel IBD Research and Drug Development

Creative Biogene is proud to offer a range of TNFSF15-related products designed to support researchers in their studies on inflammatory bowel disease (IBD) and drug development. These products include knockdown and overexpression cell lines, preformed viral particles, and virus-like particles.

• Transfected stable cell lines

Our company provides both knockdown and overexpression cell lines targeting the TNFSF15 gene. These cell lines can be used to investigate the functional role of TNFSF15 in IBD pathogenesis, including its impact on inflammation, immune response, and epithelial barrier function. On the other hand, our overexpression cell lines are engineered to stably express higher levels of TNFSF15. These cell lines allow researchers to study the effects of TNFSF15 overexpression on cellular processes relevant to IBD, such as cytokine production, cell proliferation, and apoptosis. They are valuable tools for exploring the potential therapeutic implications of modulating TNFSF15 expression in IBD.

View more of our transfected stable cell lines.

• Premade virus particles

We offer premade virus particles containing TNFSF15, which can be used to efficiently deliver TNFSF15 into target cells. These particles are based on viral vectors, such as lentivirus or adenovirus, engineered to carry the TNFSF15 gene. Researchers can use these viral particles to introduce TNFSF15 into cell lines or primary cells, enabling the investigation of TNFSF15's biological effects in a controlled experimental setting. These particles are especially valuable for studying the impact of TNFSF15 overexpression or knockdown on cellular responses and signaling pathways relevant to IBD.

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• Virus-like particle (VLPs)

We also provide virus-like particles (VLPs) displaying TNFSF15 on their surface. These VLPs mimic the structure and antigenicity of viruses but are non-infectious. They can be used as immunogens or antigens in various applications, including antibody generation, vaccine development, and immunological studies.

View more of our virus-like particles (VLPs).

Creative Biogene is committed to providing researchers with high-quality cell lines, premade virus particles, and virus-like particles products to advance their progress in various disease mechanism studies, target validation, and drug development. Contact us to learn more about our products and services.