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TNFSF15

Official Full Name
TNF superfamily member 15
Organism
Homo sapiens
GeneID
9966
Background
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 and IL-1 alpha. This cytokine is a ligand for receptor TNFRSF25 and decoy receptor TNFRSF21/DR6. It can activate NF-kappaB and MAP kinases, 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. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2011]
Synonyms
TL1; TL1A; VEGI; TNLG1B; VEGI192A;
Bio Chemical Class
Cytokine: tumor necrosis factor
Protein Sequence
MAEDLGLSFGETASVEMLPEHGSCRPKARSSSARWALTCCLVLLPFLAGLTTYLLVSQLRAQGEACVQFQALKGQEFAPSHQQVYAPLRADGDKPRAHLTVVRQTPTQHFKNQFPALHWEHELGLAFTKNRMNYTNKFLLIPESGDYFIYSQVTFRGMTSECSEIRQAGRPNKPDSITVVITKVTDSYPEPTQLLMGTKSVCEVGSNWFQPIYLGAMFSLQEGDKLMVNVSDISLVDYTKEDKTFFGAFLL
Open
Disease
Crohn disease, Indeterminate colitis, Ulcerative colitis
Approved Drug
0
Clinical Trial Drug
3 +
Discontinued Drug
0

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Detailed Information

The TNFSF15 gene is located on human chromosome 9q32 and comprises four exons, encoding a 251-amino-acid type II transmembrane protein known as TL1A (TNF-like ligand 1A). TL1A belongs to the tumor necrosis factor (TNF) superfamily, with a conserved TNF homology domain (THD) in its extracellular region, which mediates biological activity through trimerization. Genetic polymorphism analyses have identified multiple functional single-nucleotide polymorphisms (SNPs) in the promoter and intronic regions of TNFSF15, with the rs3810936 C/T variant associated with susceptibility to various inflammatory disorders.

TL1A interacts primarily with the receptors TNFRSF25/DR3 (Death Receptor 3) and TNFRSF21/DR6 (Death Receptor 6). DR3 is predominantly expressed on lymphocytes, especially activated T cells and innate lymphoid cells, whereas DR6 is broadly expressed on endothelial cells and neurons. The binding of TL1A to its receptors triggers either apoptotic signaling through the FADD-caspase8 pathway or inflammatory responses via TRAF2-NF-κB activation. Notably, TL1A exhibits a higher binding affinity for DR3 compared to DR6, indicating DR3 as its primary functional receptor.

TNFSF15 is constitutively expressed in vascular endothelial cells but is absent in lymphocytes. Its transcription is regulated by NF-κB and AP-1, with pro-inflammatory cytokines such as TNF-α and IL-1β strongly upregulating TL1A expression. Under pathological conditions, TNF receptor-associated factor 1 (TRAF1) interacts with NF-κB-inducing kinase to enhance TL1A transcription, creating an amplification loop that reinforces inflammation.

Biological Functions and Mechanisms

TNFSF15 exhibits differential regulation of blood and lymphatic vessels. In vascular endothelial cells, TL1A binding to DR3 activates the ASK1-JNK/p38 pathway, upregulating p21 and p27 to induce G1 cell cycle arrest, suppressing proliferation. TL1A also downregulates VEGFR2, inhibiting VEGF-A-mediated PI3K-Akt and FAK-Src signaling, which reduces endothelial cell migration and tube formation. In contrast, in lymphatic endothelial cells, TL1A promotes proliferation and migration via DR3-mediated activation of VEGFR3 signaling. It induces VEGF-C secretion and upregulates integrin α9β1, supporting lymphangiogenesis and facilitating tumor metastasis.

Figure 1. Signal transductioninitiatedbyTL1A/DR3.Figure 1. Signal transductioninitiatedbyTL1A/DR3. ( Xu WD, et al., 2022)

TL1A is a critical regulator of adaptive immunity. In CD4+ T cells, TL1A-DR3 signaling preferentially promotes Th1 and Th17 differentiation by activating STAT3 and STAT4, inducing T-bet and RORγt expression. In innate lymphoid cells, TL1A-DR3 stimulation induces type 2 immune responses, enhancing IL-5, IL-13, and GM-CSF secretion. This axis forms a pro-inflammatory feedback loop in mucosal tissues and contributes to allergic inflammation, with targeted inhibition reducing immune-mediated tissue damage.

TL1A induces apoptosis through both death-domain-dependent and independent pathways. In activated lymphocytes, TL1A-DR3 interaction recruits FADD and caspase-8 to form the death-inducing signaling complex, activating caspase cascades. In endothelial cells, TL1A triggers mitochondrial apoptosis by upregulating Bim and Bid and downregulating Mcl-1, leading to cytochrome c release. Its pro-apoptotic effects are context-dependent: in the presence of TNF-α, apoptosis is enhanced, whereas VEGF stimulation can confer protective effects.

Physiological and Pathological Relevance

TL1A has dual roles in tumor vascular biology. It can inhibit angiogenesis by suppressing endothelial proliferation and downregulating pro-angiogenic factors, thereby restricting tumor growth. Conversely, TL1A promotes lymphangiogenesis and metastasis by stimulating lymphatic endothelial cells via VEGFR3 signaling, contributing to tumor dissemination. These contrasting effects highlight the context-specific role of TL1A in the tumor microenvironment.

Polymorphisms in TNFSF15 are linked to increased susceptibility to inflammatory diseases. Elevated TL1A expression in intestinal mucosa amplifies Th1 and Th17 responses, contributing to conditions such as inflammatory bowel disease. TL1A also participates in cholangiopathies by activating portal CD4+ T cells and ILC2, promoting epithelial injury. Its expression correlates with disease severity and may serve as a biomarker for monitoring activity and therapeutic response.

TL1A drives fibrosis through activation of fibroblasts and endothelial-to-mesenchymal transition. In systemic sclerosis, TL1A-positive macrophages correlate with skin fibrosis severity, while in idiopathic pulmonary fibrosis, alveolar TL1A recruits fibroblasts and promotes extracellular matrix deposition, contributing to progressive tissue remodeling.

Clinical Applications and Translational Research

Soluble TL1A (sTL1A) serves as a marker for disease activity and therapeutic response. Elevated serum TL1A levels correlate with disease severity in inflammatory and fibrotic conditions, and may help predict responsiveness to biologic therapies. In oncology, high TNFSF15 expression is associated with adverse prognosis, reflecting its role in tumor microenvironment modulation.

Therapeutic strategies targeting TNFSF15 include monoclonal antibodies against TL1A, DR3-Fc fusion proteins acting as decoy receptors, small molecules inhibiting TL1A trimerization, and antisense oligonucleotides regulating promoter activity. These interventions have shown efficacy in preclinical and early clinical models, providing selective modulation of inflammation and vascular function.

Recombinant TL1A exhibits potential in ocular neovascular disorders and tumor therapy by simultaneously inhibiting endothelial proliferation and VEGFR2 signaling, achieving dual effects on angiogenesis and lymphangiogenesis. Gene therapy approaches combining TL1A expression with chemotherapeutic regimens demonstrate enhanced tumor control and microvascular reduction.

The major challenges in TNFSF15 research arise from its context-dependent dual functions in vascular and lymphatic systems. Addressing this requires tissue-specific delivery systems, conditional activation strategies, and careful modulation of DR3 signaling. Future research should focus on single-cell multi-omics mapping of TL1A-responsive cells, dual-function fusion proteins targeting angiogenesis and lymphangiogenesis, and precise gene regulation approaches using CRISPR-based tools. Continued investigation promises to unlock the full therapeutic potential of TNFSF15 in cancer, autoimmune diseases, and fibrosis, enabling precise and targeted clinical interventions.

Reference

  1. Xu WD, Li R, Huang AF. Role of TL1A in Inflammatory Autoimmune Diseases: A Comprehensive Review. Front Immunol. 2022 Jul 14;13:891328.
  2. Bamias G, Menghini P, Pizarro TT, et al. Targeting TL1A and DR3: the new frontier of anti-cytokine therapy in IBD. Gut. 2025 Mar 6;74(4):652-668.
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