Alternative titles; symbols
HGNC Approved Gene Symbol: TNFSF15
Cytogenetic location: 9q32 Genomic coordinates (GRCh38) : 9:114,784,635-114,806,039 (from NCBI)
Members of the tumor necrosis factor (TNF; 191160) and TNF receptor (TNFR) superfamilies regulate diverse biologic functions, including cell proliferation, immune regulation, and inflammation. See 191190.
By searching a human sequence database, Tan et al. (1997) identified cDNAs encoding several TNF ligand-related (TL) and TNFR-related (TR) proteins. Northern blot analysis revealed that TL1 was expressed as multiple mRNAs in most tissues tested and in primary arterial endothelial cells and monocytes. However, TL1 was not expressed in either B or T cells.
Independently, Zhai et al. (1999) cloned cDNAs corresponding to the same gene, which they called VEGI for 'vascular endothelial growth inhibitor.' They reported that the predicted 174-amino acid protein has the characteristic structure of a type II transmembrane protein, with an extracellular C terminus, a single transmembrane domain, and a short cytoplasmic tail. Like other members of the TNF family, VEGI shares 20 to 30% sequence identity with TNF and FAS ligand (134638).
Migone et al. (2002) identified a full-length variant of TL1, which they termed TL1A, by EST database searching and screening of an endothelial cell cDNA library. The deduced 251-amino acid protein is approximately 65% homologous to the mouse and rat Tl1a sequences. RT-PCR analysis detected predominant expression in endothelial cells and showed that TL1A is more abundant than TL1. TL1A expression was highly inducible by TNF and interleukin-1-alpha (IL1A; 147760), but not by gamma-interferon (IFNG; 147570). By screening a cell line expressing TL1A with TNFR family fusion proteins, Migone et al. (2002) identified death receptor-3 (DR3, or TNFRSF25; 603366) and decoy receptor-3 (DCR3, or TNFRSF6B; 603361) as receptors for TL1A in both their soluble and membrane-bound forms.
By genomic sequence analysis, Migone et al. (2002) determined that the TNFSF15 gene contains 4 coding exons.
By analysis of radiation hybrids, Tan et al. (1997) mapped the TL1 gene to 9q32, near the CD30L (TNFSF8; 603875) gene at 9q33. Zhai et al. (1999) confirmed this map position using FISH.
Zhai et al. (1999) found that expression of a recombinant soluble form of VEGI inhibited the growth of colon carcinomas in mice, and the tumors expressing the soluble VEGI had markedly reduced vascularization. Conditioned media from cells expressing soluble VEGI dramatically inhibited proliferation of bovine aortic endothelial cells. Zhai et al. (1999) concluded that VEGI is an angiogenesis inhibitor that functions in part by directly inhibiting endothelial cell proliferation. Yue et al. (1999) reported that TL1 causes endothelial cell apoptosis via activation of the stress protein kinases SAPK/JNK (see 601158) and p38 MAPK (see 600289) and the caspases, primarily caspase-3 (600636).
By functional analysis, Migone et al. (2002) showed that TL1A, but not TL1, induces nuclear factor kappa-B (NFKB; see 164011) activation in cells expressing DR3. Exposure of T lymphocytes, but not other cells, to TL1A enhanced IL2 receptor-alpha (IL2RA; 147730) and IL2 receptor-beta (IL2RB; 146710) expression on these cells, increased proliferation in response to IL2 (147680), and induced secretion of IFNG and granulocyte-macrophage colony-stimulating factor (GMCSF, or CSF2; 138960), but not other cytokines, especially in the presence of anti-CD28 (186760) costimulation. Exposure of an erythroleukemic cell line (TF-1), but not activated T cells, to TL1A induced caspase activation and cell death, particularly when protein synthesis was inhibited. Migone et al. (2002) showed that treatment of mice with recombinant TL1A strongly enhanced graft-versus-host reactivity, consistent with DR3 being mainly expressed on activated T cells.
By studying intestinal tissue specimens and isolated lamina propria mononuclear cells from patients with inflammatory bowel disease (IBD; see 266600) and controls, Bamias et al. (2003) detected upregulated TL1A mRNA and protein expression in involved tissues from Crohn disease patients, notably in lamina propria macrophages and CD4 (186940)-positive and CD8 (see 186910)-positive lymphocytes. In ulcerative colitis patients, upregulated expression was also detected in plasma cells. TL1A protein amount and TL1A-positive cell numbers correlated with severity of inflammation. Immunohistochemical analysis showed increased numbers of T lymphocytes positive for DR3 in intestinal lamina propria of IBD patients. Bamias et al. (2003) concluded that expression of TL1A and its receptor is upregulated in IBD. Furthermore, the results showed that TL1A expression occurs in lymphocytes and macrophages in addition to endothelial cells.
Using Dr3-deficient mice, Meylan et al. (2008) identified Dr3 as the receptor responsible for Tl1a-induced T-cell costimulation and dendritic cells as the likely source for Tl1a during T-cell activation. Dr3 was not required for in vivo T-cell priming, for polarization into Th1, Th2, or Th17 effector cell subtypes, or for effective control of Toxoplasma gondii infection. However, it was required on T cells for immunopathology, local T accumulation, and cytokine production in the inflammatory disease models experimental autoimmune encephalomyelitis and allergic lung inflammation.
Using T cells from Tradd (603500) -/- mice, Pobezinskaya et al. (2011) demonstrated that the proliferative response of both Cd4 and Cd8 T cells to Tl1a was dependent on Tradd. Stimulation of MAP kinase signaling and activation of NF-kappa-B in response to Tl1a were also dramatically reduced in Tradd -/- T cells. Tradd was required for recruitment of Rip1 (RIPK1; 603453) and Traf2 (601895) to the Dr3 signaling complex and for ubiquitination of Rip1. Pobezinskaya et al. (2011) concluded that TRADD is essential in TL1A-DR3 signaling.
For a discussion of a possible association between SNPs in the TNFSF15 gene and Crohn disease, see IBD16 (612259).
Using 2 mouse models of Crohn disease (CD), Bamias et al. (2006) found increased expression of transmembrane Dr3 and Tl1A mRNA in inflamed ileum compared with tissue from age-matched wildtype controls and young, uninflamed CD-susceptible mice. Flow cytometry and confocal microscopy demonstrated expression of Tl1a on lamina propria mononuclear cells.
Fang et al. (2008) found that antibody blockade of the Tnfr25 ligand Tnf15 or expression of a Tnfr25 dominant-negative transgene inhibited lung inflammation and the production of Th2 cytokines, such as Il13 (147683), in mice. The antibody was effective even when administered days after airway antigen exposure. Mice deficient in natural killer T (NKT) cells and resistant to allergic lung inflammation became susceptible upon adoptive transfer of wildtype NKT cells, but not upon transfer of dominant-negative Tnfr25 transgenic NKT cells. Fang et al. (2008) concluded that the TNFR25/TNF15 pair provides an early signal for Th2 cytokine production in lung and may be a drug target for attempts to attenuate lung inflammation in asthmatics.
Bamias, G., Martin, C., III, Marini, M., Hoang, S., Mishina, M., Ross, W. G., Sachedina, M. A., Friel, C. M., Mize, J., Bickston, S. J., Pizarro, T. T., Wei, P., Cominelli, F. Expression, localization, and functional activity of TL1A, a novel Th1-polarizing cytokine in inflammatory bowel disease. J. Immun. 171: 4868-4874, 2003. [PubMed: 14568967] [Full Text: https://doi.org/10.4049/jimmunol.171.9.4868]
Bamias, G., Mishina, M., Nyce, M., Ross, W. G., Kollias, G., Rivera-Nieves, J., Pizarro, T. T., Cominelli, F. Role of TL1A and its receptor DR3 in two models of chronic murine ileitis. Proc. Nat. Acad. Sci. 103: 8441-8446, 2006. [PubMed: 16698931] [Full Text: https://doi.org/10.1073/pnas.0510903103]
Fang, L., Adkins, B., Deyev, V., Podack, E. R. Essential role of TNF receptor superfamily 25 (TNFRSF25) in the development of allergic lung inflammation. J. Exp. Med. 205: 1037-1048, 2008. [PubMed: 18411341] [Full Text: https://doi.org/10.1084/jem.20072528]
Meylan, F., Davidson, T. S., Kahle, E., Kinder, M., Acharya, K., Jankovic, D., Bundoc, V., Hodges, M., Shevach, E. M., Keane-Myers, A., Wang, E. C. Y., Siegel, R. M. The TNF-family receptor DR3 is essential for diverse T cell-mediated inflammatory diseases. Immunity 29: 79-89, 2008. [PubMed: 18571443] [Full Text: https://doi.org/10.1016/j.immuni.2008.04.021]
Migone, T.-S., Zhang, J., Luo, X., Zhuang, L., Chen, C., Hu, B., Hong, J. S., Perry, J. W., Chen, S.-F., Zhou, J. X. H., Cho, Y. H., Ullrich, S., and 14 others. TL1A is a TNF-like ligand for DR3 and TR6/DcR3 and functions as a T cell costimulator. Immunity 16: 479-492, 2002. [PubMed: 11911831] [Full Text: https://doi.org/10.1016/s1074-7613(02)00283-2]
Pobezinskaya, Y. L., Choksi, S., Morgan, M. J., Cao, X., Liu, Z. The adaptor protein TRADD is essential for TNF-like ligand 1A/death receptor 3 signaling. J. Immun. 186: 5212-5216, 2011. [PubMed: 21421854] [Full Text: https://doi.org/10.4049/jimmunol.1002374]
Tan, K. B., Harrop, J., Reddy, M., Young, P., Terrett, J., Emery, J., Moore, G., Truneh, A. Characterization of a novel TNF-like ligand and recently described TNF ligand and TNF receptor superfamily genes and their constitutive and inducible expression in hematopoietic and non-hematopoietic cells. Gene 204: 35-46, 1997. [PubMed: 9434163] [Full Text: https://doi.org/10.1016/s0378-1119(97)00509-x]
Yue, T.-L., Ni, J., Romanic, A. M., Gu, J.-L., Keller, P., Wang, C., Kumar, S., Yu, G., Hart, T. K., Wang, X., Xia, Z., DeWolf, W. E., Jr., Feuerstein, G. Z. TL1, a novel tumor necrosis factor-like cytokine, induces apoptosis in endothelial cells: involvement of activation of stress protein kinases (stress-activated protein kinase and p38 mitogen-activated protein kinase) and caspase-3-like protease. J. Biol. Chem. 274: 1479-1486, 1999. [PubMed: 9880523] [Full Text: https://doi.org/10.1074/jbc.274.3.1479]
Zhai, Y., Ni, J., Jiang, G.-W., Lu, J., Xing, L., Lincoln, C., Carter, K. C., Janat, F., Kozak, D., Xu, S., Rojas, L., Aggarwal, B. B., Ruben, S., Li, L.-Y., Gentz, R., Yu, G.-L. VEGI, a novel cytokine of the tumor necrosis factor family, is an angiogenesis inhibitor that suppresses the growth of colon carcinomas in vivo. FASEB J. 13: 181-189, 1999. [PubMed: 9872942] [Full Text: https://doi.org/10.1096/fasebj.13.1.181]