TL1A is a type II transmembrane protein belonging to the TNF superfamily and has been designated TNF superfamily member 15 (TNFSF15). Mouse TL1A is a 252 amino acid residues (aa) protein consisting of a 35 aa N-terminal cytoplasmic domain, a 24 aa transmembrane region and 193 aa C-terminal extracellular domain. TL1A is expressed predominantly in endothelial cells and its expression is stimulated by TNF-a and IL-1a. Non-endothelial cells of the gut mucosa, including lamina propria lymphocytes and tissue macrophages, also express TL1A and at higher levels in chronic inflammatory bowel disorders . TL1A binds with high affinity to death receptor 3 (DR3), which is now designated TNF receptor superfamily member 25 (TNFRSF25). DR3 was formerly designated TNFRSF12 when it was thought to be the receptor for TWEAK/TNFSF12. Depending on the cell type, DR3-TL1A interactions have different effects. Ligation of DR3 on activated T cells by TL1A provides a costimulatory signal to increase IL-2 responsiveness and the secretion of proinflamatory cytokines . The promotion of survival of activated T cells by TL1a results from the activation of the transcription factor NF-kappa-B. In a tumor erythroleukemic cell line, TF-1, DR3-TL1A signaling increases production of the NF-kB-dependent antiapoptotic protein c-IAP2, promoting survival in these cells . In HUVEC cells, which express both DR3 and TL1A, ligation of DR3 by TL1A regulates cell apoptosis . These effects of TL1A are blocked by the secreted, soluble decoy receptor 3 (DcR3), also known as TR6 and TNFRSF6B, which compete with DR3 for binding to TL1A . Consistent with the observed in vitro activities, TL1A promotes ex vivo splenocyte expansion and enhances in vivo graft-versus-host-response. The level of TL1A in cells of gut mucosa, in patients with bowel inflammatory disorders, correlates with the severity of inflammation, and TL1A may play a role in a Th1-mediate pathological conditions such as Crohn’s disease .
