Disease relevance of TNFSF15

• Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn's disease [1].
• The purpose of this study was to assess the role of recombinant TL1A on IFN-gamma production by cultured PBMC and lamina propria LPMC and to determine whether TL1A expression is altered in inflammatory bowel disease [2].
• A higher fraction of cells also express the TL1A receptor DR3 in ulcerative colitis and Crohn's disease [2].
• Involvement of TL1A and DR3 in induction of pro-inflammatory cytokines and matrix metalloproteinase-9 in atherogenesis [3].
• Local production of a secreted form of VEGI via gene transfer caused complete suppression of the growth of MC-38 murine colon cancers in syngeneic C57BL/6 mice [4].

High impact information on TNFSF15

• Interestingly, in T cells, TL1A acts as a costimulator that increases IL-2 responsiveness and secretion of proinflammatory cytokines both in vitro and in vivo [5].
• We identified highly significant associations (P = 1.71 x 10(-14) with odds ratio of 2.17) of SNPs and haplotypes within the TNFSF15 (the gene encoding tumor necrosis factor superfamily, member 15) genes in Japanese CD patients [1].
• Interestingly, a core TNFSF15 haplotype showing association with increased risk to the disease was common in the two ethnic groups [1].
• A previous study shows TL1A is able to interact with death receptor 3 and decoy receptor 3 (DcR3) [6].
• These data demonstrate DcR3 might not only help tumor cells to escape immune surveillance but also induce angiogenesis by blocking TL1A action in endothelial cells [6].

Biological context of TNFSF15

• These findings support the view that endothelial cell-secreted VEGI may function as an autocrine inhibitor of angiogenesis and a naturally existing modulator of vascular homeostasis [7].
• Furthermore, inhibition of c-IAP2 production by RNA interference significantly sensitized TF-1 cells to TL1A-induced apoptosis [8].
• The ability to augment TRAIL-initiated cell death was not observed with soluble lymphotoxin beta receptor or soluble death receptor 3, indicating that binding to LIGHT or TL1A alone is insufficient to trigger TRAIL sensitivity [9].
• The VEGI gene was mapped to human chromosome 9q32 [4].
• In contrast, human aortic endothelial cells, which do not express TL1A, are not responsive to DcR3 treatment, including cell proliferation, migration, and angiogenic differentiation [6].

Anatomical context of TNFSF15

• VEGI-192, a new isoform of TNFSF15, specifically eliminates tumor vascular endothelial cells and suppresses tumor growth [10].
• In the intestinal mucosa, a fraction of lamina propria (LP) T cells, especially CD4+ cells, constitutively expressed mb-TL1A, and the fraction increased in mucosal inflammation [2].
• T cell activating stimuli induced expression of TL1A on the cell membrane (mb-TL1A) in a fraction of peripheral blood (PB) T cells [2].
• Immunohistochemical staining of human carotid atherosclerotic plaques revealed a high-level expression of TL1A in regions rich in macrophage/foam cells [3].
• Furthermore, we demonstrate that TL1A production in monocytes leads to enhancement of T cell responses [11].

Associations of TNFSF15 with chemical compounds

• Vascular endothelial cell growth inhibitor (VEGI), a member of the tumor necrosis factor (TNF) family, is an endothelial cell-specific inhibitor of angiogenesis [7].
• Consistent with this, we found that TL1A significantly increased the production of c-IAP2, a known NF-kappaB-dependent anti-apoptotic protein, and that the NF-kappaB inhibitor or cycloheximide prevented its synthesis [8].
• TL1-induced apoptosis in the BPAEC was reduced by expression of a dominant-interfering mutant of c-Jun (62.8%, p < 0.05) or by a specific p38 inhibitor, SB203580 (1-10 microM) dose-dependently [12].
• Accordingly, in vitro experiments revealed that human monocytes express and release significant amounts of soluble TL1A when stimulated with insoluble immune complexes (IC), polyethylene glycol precipitates from the serum of RF+/RA patients, or with insoluble ICs purified from RA synovial fluids [13].

Regulatory relationships of TNFSF15

• A newly discovered TNF-superfamily cytokine (TL1A) could also be involved in initiating or promoting the Th1 response by enhancing IFN-gamma production [2].
• TL1A-induced NF-kappaB activation and c-IAP2 production prevent DR3-mediated apoptosis in TF-1 cells [8].
• Moreover, DcR3-induced cell adhesion could be detected in human aortic endothelial cells (ECs) in which TL1A expression is lacking [14].
• In addition, VEGI activated c-Jun N-terminal kinase [15].
• TL1A induces interleukin-8 (IL-8) secretion in human peripheral blood monocyte-derived macrophage in a dose- and time-dependent manner [16].

Other interactions of TNFSF15

• Potential role for TL1A, the new TNF-family member and potent costimulator of IFN-gamma, in mucosal inflammation [2].
• However, TL1A or an agonistic DR3 monoclonal antibody did not induce apoptosis in these cells nor were there detectable levels of FADD or procaspase-8 seen in the signaling complex [8].
• We recently identified TL1A, an endothelium-derived T cell costimulator and a ligand for tumor necrosis factor receptor superfamily members DR3 and decoy receptor 3 [8].
• It binds to Fas ligand, LIGHT, and TL1A, all of which are TNF family members [17].
• In the current study we show that TL1A or an agonistic anti-DR3 mAb synergize with IL-12/IL-18 to augment IFN-gamma production in human peripheral blood T cells and NK cells [18].

Analytical, diagnostic and therapeutic context of TNFSF15

• Overexpression by cancer cells of a secretable VEGI fusion protein resulted in abrogation of xenograft tumor progression, but overexpression of full-length VEGI was completely without effect [7].
• FcgammaR stimulation strongly induced TL1A mRNA in both cell types, which correlated with the detection of TL1A on the cell surface and in cell culture medium [11].
• Taken together, our results indicated that ELISA might be useful in studying soluble TL1A regulation in certain inflammatory conditions [19].
• The VEGI expression profile was assessed qualitatively (RT-PCR), quantitatively (real-time Quantitative-PCR), and immuno-histochemically (IHC), in a panel of 24 human normal and cancer cell lines and in a cohort of 151 mammary tissue samples (n = 33 normal breast tissue; n = 118 breast cancer tissue) with a 6-year median follow-up [20].

References