Vascular endothelial growth inhibitor explained

Vascular endothelial growth inhibitor (VEGI), also known as TNF-like ligand 1A (TL1A) and TNF superfamily member 15 (TNFSF15), is protein that in humans is encoded by the TNFSF15 gene. VEGI is an anti-angiogenic protein.^[1] It belongs to tumor necrosis factor (ligand) superfamily, where it is member 15.^[2] It is the sole known ligand for death receptor 3,^[3] and it can also be recognized by decoy receptor 3.

Function

The protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This protein is abundantly expressed in endothelial cells, but is not expressed in either B or T cells. The expression of this protein is inducible by TNF-alpha and IL-1 alpha. This cytokine is a ligand for receptor TNFRSF25 (death receptor 3) and TNFRSF6B (decoy receptor 3). It can activate both the NF-κB and MAPK signalling pathways, and acts as an autocrine factor to induce apoptosis in endothelial cells. This cytokine is also found to inhibit endothelial cell proliferation, and thus may function as an angiogenesis inhibitor. An additional isoform encoded by an alternatively spliced transcript variant has been reported but the sequence of this transcript has not been determined.

Clinical relevance

Several TNFSF15 SNPs have been found to be strongly associated with inflammatory bowel disease.^{[4] [5]}

References

Further reading

• Tan KB, 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 . 1–2 . 35–46 . Dec 1997 . 9434163 . 10.1016/s0378-1119(97)00509-x .
• Zhai Y, Ni J, Jiang GW, Lu J, Xing L, Lincoln C, Carter KC, Janat F, Kozak D, Xu S, Rojas L, Aggarwal BB, Ruben S, Li LY, Gentz R, Yu GL . VEGI, a novel cytokine of the tumor necrosis factor family, is an angiogenesis inhibitor that suppresses the growth of colon carcinomas in vivo . FASEB Journal . 13 . 1 . 181–9 . Jan 1999 . 9872942 . 10.1096/fasebj.13.1.181. free . 26066673 .
• Yue TL, Ni J, Romanic AM, Gu JL, Keller P, Wang C, Kumar S, Yu GL, Hart TK, Wang X, Xia Z, DeWolf WE, Feuerstein GZ . 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 . The Journal of Biological Chemistry . 274 . 3 . 1479–86 . Jan 1999 . 9880523 . 10.1074/jbc.274.3.1479 . free .
• Haridas V, Shrivastava A, Su J, Yu GL, Ni J, Liu D, Chen SF, Ni Y, Ruben SM, Gentz R, Aggarwal BB . VEGI, a new member of the TNF family activates nuclear factor-kappa B and c-Jun N-terminal kinase and modulates cell growth . Oncogene . 18 . 47 . 6496–504 . Nov 1999 . 10597252 . 10.1038/sj.onc.1203059 . 7013492 .
• Yu J, Tian S, Metheny-Barlow L, Chew LJ, Hayes AJ, Pan H, Yu GL, Li LY . Modulation of endothelial cell growth arrest and apoptosis by vascular endothelial growth inhibitor . Circulation Research . 89 . 12 . 1161–7 . Dec 2001 . 11739281 . 10.1161/hh2401.101909 . free .
• Migone TS, Zhang J, Luo X, Zhuang L, Chen C, Hu B, Hong JS, Perry JW, Chen SF, Zhou JX, Cho YH, Ullrich S, Kanakaraj P, Carrell J, Boyd E, Olsen HS, Hu G, Pukac L, Liu D, Ni J, Kim S, Gentz R, Feng P, Moore PA, Ruben SM, Wei P . TL1A is a TNF-like ligand for DR3 and TR6/DcR3 and functions as a T cell costimulator . Immunity . 16 . 3 . 479–92 . Mar 2002 . 11911831 . 10.1016/S1074-7613(02)00283-2 . free .
• Chew LJ, Pan H, Yu J, Tian S, Huang WQ, Zhang JY, Pang S, Li LY . A novel secreted splice variant of vascular endothelial cell growth inhibitor . FASEB Journal . 16 . 7 . 742–4 . May 2002 . 11923219 . 10.1096/fj.01-0757fje . free . 34749634 .
• Wen L, Zhuang L, Luo X, Wei P . TL1A-induced NF-kappaB activation and c-IAP2 production prevent DR3-mediated apoptosis in TF-1 cells . The Journal of Biological Chemistry . 278 . 40 . 39251–8 . Oct 2003 . 12882979 . 10.1074/jbc.M305833200 . free .
• Bamias G, Martin C, Marini M, Hoang S, Mishina M, Ross WG, Sachedina MA, Friel CM, Mize J, Bickston SJ, Pizarro TT, Wei P, Cominelli F . Expression, localization, and functional activity of TL1A, a novel Th1-polarizing cytokine in inflammatory bowel disease . Journal of Immunology . 171 . 9 . 4868–74 . Nov 2003 . 14568967 . 10.4049/jimmunol.171.9.4868 . free .
• Prehn JL, Mehdizadeh S, Landers CJ, Luo X, Cha SC, Wei P, Targan SR . Potential role for TL1A, the new TNF-family member and potent costimulator of IFN-gamma, in mucosal inflammation . Clinical Immunology . 112 . 1 . 66–77 . Jul 2004 . 15207783 . 10.1016/j.clim.2004.02.007 .
• Kang YJ, Kim WJ, Bae HU, Kim DI, Park YB, Park JE, Kwon BS, Lee WH . Involvement of TL1A and DR3 in induction of pro-inflammatory cytokines and matrix metalloproteinase-9 in atherogenesis . Cytokine . 29 . 5 . 229–35 . Mar 2005 . 15760679 . 10.1016/j.cyto.2004.12.001 .
• Hou W, Medynski D, Wu S, Lin X, Li LY . VEGI-192, a new isoform of TNFSF15, specifically eliminates tumor vascular endothelial cells and suppresses tumor growth . Clinical Cancer Research . 11 . 15 . 5595–602 . Aug 2005 . 16061878 . 10.1158/1078-0432.CCR-05-0384 . free .
• Yamazaki K, McGovern D, Ragoussis J, Paolucci M, Butler H, Jewell D, Cardon L, Takazoe M, Tanaka T, Ichimori T, Saito S, Sekine A, Iida A, Takahashi A, Tsunoda T, Lathrop M, Nakamura Y . Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn's disease . Human Molecular Genetics . 14 . 22 . 3499–506 . Nov 2005 . 16221758 . 10.1093/hmg/ddi379 . free .
• Yao JJ, Zhang M, Miao XH, Zhao P, Zhu SY, Ding H, Qi ZT . Isoform of vascular endothelial cell growth inhibitor (VEGI72-251) increases interleukin-2 production by activation of T lymphocytes . Acta Biochimica et Biophysica Sinica . 38 . 4 . 249–53 . Apr 2006 . 16604264 . 10.1111/j.1745-7270.2006.00155.x .
• Prehn JL, Thomas LS, Landers CJ, Yu QT, Michelsen KS, Targan SR . The T cell costimulator TL1A is induced by FcgammaR signaling in human monocytes and dendritic cells . Journal of Immunology . 178 . 7 . 4033–8 . Apr 2007 . 17371957 . 10.4049/jimmunol.178.7.4033 . free .
• Cassatella MA, Pereira-da-Silva G, da Silva GP, Tinazzi I, Facchetti F, Scapini P, Calzetti F, Tamassia N, Wei P, Nardelli B, Roschke V, Vecchi A, Mantovani A, Bambara LM, Edwards SW, Carletto A . Soluble TNF-like cytokine (TL1A) production by immune complexes stimulated monocytes in rheumatoid arthritis . Journal of Immunology . 178 . 11 . 7325–33 . Jun 2007 . 17513783 . 10.4049/jimmunol.178.11.7325 . free .
• Jin T, Guo F, Kim S, Howard A, Zhang YZ . X-ray crystal structure of TNF ligand family member TL1A at 2.1A . Biochemical and Biophysical Research Communications . 364 . 1 . 1–6 . Dec 2007 . 17935696 . 10.1016/j.bbrc.2007.09.097 .

Notes and References

1. Hoffmann R, Valencia A . A gene network for navigating the literature . Nature Genetics . 36 . 7 . 664 . Jul 2004 . 15226743 . 10.1038/ng0704-664 . free .
2. Web site: Entrez Gene: TNFSF15 tumor necrosis factor (ligand) superfamily, member 15.
3. Wang EC . On death receptor 3 and its ligands… . Immunology . 137 . 1 . 114–116 . Sep 2012 . 22612445 . 3449252 . 10.1111/j.1365-2567.2012.03606.x .
4. Picornell Y, Mei L, Taylor K, Yang H, Targan SR, Rotter JI . TNFSF15 is an ethnic-specific IBD gene . Inflammatory Bowel Diseases . 13 . 11 . 1333–8 . Nov 2007 . 17663424 . 2552994 . 10.1002/ibd.20223 .
5. Kakuta Y, Kinouchi Y, Negoro K, Takahashi S, Shimosegawa T . Association study of TNFSF15 polymorphisms in Japanese patients with inflammatory bowel disease . Gut . 55 . 10 . 1527–8 . Oct 2006 . 16966713 . 1856432 . 10.1136/gut.2006.100297 .