Affinage

TNFSF15

Tumor necrosis factor ligand superfamily member 15 · UniProt O95150

Length
251 aa
Mass
28.1 kDa
Annotated
2026-04-28
100 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TNFSF15 (TL1A) is a TNF superfamily cytokine that functions as a pleiotropic immune regulator, anti-angiogenic factor, and pro-fibrotic mediator through engagement of its signaling receptor DR3 (TNFRSF25) and decoy receptor DcR3. Binding to DR3 recruits TRADD, TRAF2, and RIP to activate NF-κB, MAPK (ERK/JNK/p38), and PI3K/Akt pathways, with NF-κB-dependent c-IAP2 upregulation preventing apoptosis in some contexts while FADD/caspase-8-containing DISC formation mediates apoptosis in others (PMID:12882979, PMID:29497138). TL1A costimulates Th1, Th17, ILC2, NK cell, Treg, and plasma cell responses in a DR3-dependent manner, synergizing with cytokines such as IL-12, IL-18, IL-23, and IL-33 to amplify effector functions including IFN-γ, IL-17, IL-13, and IL-9 production, while also driving intestinal fibrosis through direct Rho pathway activation in DR3-expressing fibroblasts (PMID:15153521, PMID:18411337, PMID:24368564, PMID:38597952, PMID:24140642, PMID:33097818). TL1A expression in antigen-presenting cells is induced by FcγR/immune complex signaling and microbial TLR-p38 MAPK-NF-κB pathways, and disease-risk SNPs create NF-1 binding sites that increase TNFSF15 transcription, amplifying PRR-induced inflammatory and antimicrobial outcomes including ROS, NOS2, and autophagy (PMID:17371957, PMID:19839006, PMID:25899471, PMID:32827707).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2002 High

    The identification of TL1A as the ligand for DR3 and decoy receptor DcR3 established the fundamental receptor-ligand axis, demonstrating that DR3 engagement activates NF-κB, induces apoptosis, and costimulates T cell cytokine production.

    Evidence Receptor-ligand binding assays, NF-κB reporter assays, apoptosis assays, and T cell functional assays in vitro and in vivo

    PMID:11911831

    Open questions at the time
    • Downstream signaling intermediates between DR3 and NF-κB/apoptosis not yet defined
    • In vivo physiological role of TL1A not established
    • Mechanism of DcR3 decoy function unclear
  2. 2003 High

    Defining the DR3 proximal signaling complex (TRADD/TRAF2/RIP) and its bifurcation into NF-κB-mediated survival (via c-IAP2) versus apoptosis resolved how TL1A-DR3 signaling produces opposing cell fate outcomes.

    Evidence Co-immunoprecipitation, NF-κB reporter assays, MAPK inhibitors, siRNA knockdown of c-IAP2, apoptosis assays in TF-1 cells

    PMID:12882979

    Open questions at the time
    • Whether FADD/caspase-8 DISC forms downstream of DR3 not yet shown
    • Signaling in primary immune cells not addressed
    • Context-dependent fate decision mechanism not resolved
  3. 2004 High

    Demonstration that TL1A synergizes with IL-12/IL-18 to amplify IFN-γ from T cells and NK cells, and that TL1A exerts angiostatic effects by inducing DR3-dependent endothelial cell apoptosis, revealed TL1A as both a lymphocyte costimulator and anti-angiogenic factor.

    Evidence Cytokine stimulation and intracellular staining of T/NK cells; endothelial cell proliferation, migration, tube formation, and in vivo neovascularization assays with neutralizing antibodies

    PMID:14871847 PMID:15153521

    Open questions at the time
    • In vivo role of TL1A in angiogenesis regulation not tested genetically
    • Whether TL1A costimulation extends to Th17 or other T cell subsets unknown
    • Mechanism of endothelial apoptosis downstream of DR3 not defined
  4. 2007 High

    Identification of FcγR/immune complex signaling as the primary inducer of TL1A in monocytes and dendritic cells established how adaptive immune responses generate TL1A to amplify T cell activation.

    Evidence Stimulation of monocytes/DCs with FcγR and TLR agonists, surface and secreted TL1A detection, T cell co-culture

    PMID:17371957

    Open questions at the time
    • Role of TLR pathways in TL1A induction debated (later resolved)
    • Regulation of membrane-bound versus soluble TL1A not addressed
    • Whether FcγR-induced TL1A is relevant in vivo not shown
  5. 2008 High

    TL1A knockout mice and anti-TL1A neutralizing antibodies demonstrated that TL1A-DR3 signaling costimulates both Th1 and Th17 responses in vivo and is required for full disease severity in EAE and chronic colitis, establishing TL1A as a therapeutic target in autoimmune inflammation.

    Evidence TL1A KO mice in EAE; anti-TL1A antibody in DSS chronic colitis and T cell transfer colitis; Th17 differentiation and cytokine assays

    PMID:18411337 PMID:18598698

    Open questions at the time
    • Direct effects on fibroblasts and non-immune cells not yet explored
    • Whether TL1A acts on innate lymphoid cells unknown
    • Context-dependent Th17-inhibitory effects of TL1A not yet described
  6. 2009 High

    Crystal structure of TL1A revealed the TNF jelly-roll fold and defined the DR3/DcR3 binding interface, while parallel studies showed TL1A induces DR3-dependent apoptosis of differentiated endothelial progenitor cells and that bacterial stimuli induce TL1A via TLR-p38-NF-κB signaling in APCs.

    Evidence X-ray crystallography at 2.5 Å with mutagenesis; EPC differentiation/apoptosis assays with DR3 neutralization; bacterial stimulation of monocytes/DCs with kinase inhibitors

    PMID:19329781 PMID:19522538 PMID:19839006

    Open questions at the time
    • Full TL1A-DR3 co-crystal structure not available
    • Mechanism of stage-specific DR3 expression on EPCs unknown
    • Cross-regulation between FcγR and TLR pathways for TL1A induction only partially addressed
  7. 2010 High

    Transgenic constitutive TL1A expression demonstrated sufficiency for IL-13-dependent intestinal inflammation and Treg suppression, while studies of membrane-bound TL1A and differentially shed isoforms showed that distinct TL1A forms have different functional activities on T cells versus endothelial cells.

    Evidence TL1A transgenic mice (T cell and DC-specific); membrane-bound TL1A co-culture assays; TL1A isoform characterization in HUVECs/EPCs

    PMID:20403353 PMID:20675618 PMID:20826539 PMID:20980995

    Open questions at the time
    • Whether TL1A isoforms are differentially regulated in vivo unclear
    • Direct fibrotic mechanism not yet defined
    • Context-dependent effects on naive versus committed Th17 cells require further dissection
  8. 2013 High

    TL1A was shown to act on multiple previously unrecognized DR3-expressing target cells — ILC2s, Tregs, plasma cells, and fibroblasts — revealing breadth as a costimulatory and pro-fibrotic cytokine, and to inhibit vasculogenesis by shifting VEGFR1 splicing toward soluble sFlt1 via Jmjd6 downregulation.

    Evidence DR3 KO and TL1A transgenic mice in allergic and colitis models; TL1A-Ig fusion for Treg expansion; TL1A KO in CIA with plasma cell survival assays; EPC/Matrigel assays with siRNA and splicing analysis; fibroblast TL1A stimulation with DR3 KO

    PMID:23319737 PMID:23918400 PMID:24140642 PMID:24368564 PMID:24850426

    Open questions at the time
    • Whether ILC2/Treg/plasma cell effects are interdependent in vivo not resolved
    • Precise mechanism linking TL1A to Jmjd6 downregulation unknown
    • Relative contribution of immune versus stromal DR3 signaling to fibrosis not quantified
  9. 2014 High

    Mechanistic dissection in macrophages revealed that TACE cleaves membrane TL1A to generate soluble TL1A that drives autocrine TRADD/FADD/MALT-1/caspase-8-dependent IL-1 secretion, and that the rs6478108 IBD-risk allele increases TNFSF15 expression, providing a gain-of-function mechanism for disease susceptibility.

    Evidence Human macrophage stimulation with TACE/caspase-8 inhibitors, siRNA knockdown, risk allele genotyping; DR3 siRNA in endothelial apoptosis assays

    PMID:25161149 PMID:25197060

    Open questions at the time
    • Whether TACE is the sole sheddase for TL1A not confirmed
    • Relative contributions of autocrine versus paracrine TL1A in vivo unknown
    • Full signaling cascade from risk allele to disease phenotype not mapped
  10. 2015 High

    The disease-risk SNP rs4979462 was shown to create a novel NF-1 binding site that increases TNFSF15 transcription, and biochemical studies demonstrated that soluble TL1A trimers are sufficient to activate DR3 signaling without secondary oligomerization, distinguishing TL1A from TRAIL.

    Evidence Luciferase reporters, EMSA with supershift for NF-1, genotype-stratified mRNA/protein quantification; recombinant soluble TL1A signaling and receptor internalization assays

    PMID:25899471 PMID:26509650

    Open questions at the time
    • Whether other disease-risk variants also alter transcription factor binding not systematically tested
    • Structural basis for why TL1A trimers are sufficient (unlike TRAIL) not resolved at atomic level
  11. 2016 High

    A JNK→GATA3→miR-29b pathway was identified as the mechanism by which TL1A suppresses VEGF production in endothelial cells, connecting TL1A anti-angiogenic activity to post-transcriptional gene regulation.

    Evidence JNK inhibitor, GATA3 siRNA, miR-29b measurement, VEGF 3′-UTR reporter assays, DR3 siRNA

    PMID:27589684

    Open questions at the time
    • In vivo relevance of miR-29b-mediated VEGF suppression not tested
    • Whether this pathway operates in non-endothelial cells unknown
  12. 2017 High

    Epitope mapping by HDX-MS defined the discontinuous TL1A surface recognized by neutralizing antibodies, centering on R32 as critical for DR3 but not DcR3 binding, providing the structural rationale for selective therapeutic blockade.

    Evidence Hydrogen/deuterium exchange MS, computational modeling, competitive binding assays with DR3/DcR3 in vitro and in colitis/asthma models

    PMID:29135326 PMID:29436901

    Open questions at the time
    • Full TL1A-DR3 co-crystal structure still lacking
    • Whether R32-targeting antibodies affect all TL1A functions equally not tested
  13. 2018 High

    Discovery that antimitotic drugs induce lysosome-dependent TL1A secretion, which then engages DR3 to form a FADD/caspase-8 DISC and trigger apoptosis, established a non-immune role for TL1A-DR3 in chemotherapy-induced tumor cell death.

    Evidence Cell death assays with taxol/vinblastine, lysosomal secretion analysis, DISC pull-down, DR3 KO cell lines, xenograft models

    PMID:29497138

    Open questions at the time
    • Whether TL1A-DR3 mediates clinical antimitotic drug responses in patients unknown
    • Lysosomal secretion mechanism for TL1A not fully characterized
  14. 2020 High

    Autocrine TL1A-DR3 signaling in macrophages was shown to promote antimicrobial functions including bacterial uptake, ROS, NOS2, and autophagy through TRAF2/RIP1/RIP3, while conditional DR3 deletion in fibroblasts confirmed that direct TL1A-DR3 signaling drives intestinal fibrosis via Rho pathway activation.

    Evidence siRNA/inhibitor studies with bacterial clearance assays and genotype stratification; cell-type-specific DR3 conditional KO mice, RNA-seq, Rho inhibition

    PMID:32827707 PMID:33097818

    Open questions at the time
    • Whether antimicrobial and fibrotic TL1A pathways interact in IBD not addressed
    • Specific Rho GTPase family members mediating fibrosis not identified
  15. 2024 High

    TL1A was identified as a constitutively expressed epithelial alarmin in airway basal cells that synergizes with IL-33 to drive a transient IL-9-high ILC9 phenotype, expanding TL1A biology beyond immune cell-derived costimulation to epithelial-innate lymphoid cell crosstalk.

    Evidence Large-scale proteomics, lung intravital microscopy, adoptive ILC9 transfer, mouse allergic airway models, human airway biopsy analysis

    PMID:38597952

    Open questions at the time
    • Mechanism of constitutive TL1A expression in epithelial cells not defined
    • Whether ILC9 phenotype is relevant in intestinal or other tissue contexts unknown
    • Relationship between epithelial TL1A and APC-derived TL1A in allergic disease not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full atomic structure of the TL1A-DR3 signaling complex, the mechanisms determining whether DR3 engagement triggers survival versus apoptosis in different cell types, the identity of the sheddases and their regulation in vivo, and whether therapeutic TL1A blockade can selectively modulate pathogenic without suppressing protective antimicrobial functions.
  • No TL1A-DR3 co-crystal structure available
  • Cell-type-specific fate decision mechanism unresolved
  • In vivo sheddase regulation unknown
  • Selective therapeutic window between pathogenic and protective TL1A functions not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 6 GO:0098772 molecular function regulator activity 4
Localization
GO:0005576 extracellular region 5 GO:0005886 plasma membrane 4 GO:0005764 lysosome 1
Pathway
R-HSA-168256 Immune System 7 R-HSA-162582 Signal Transduction 5 R-HSA-5357801 Programmed Cell Death 5 R-HSA-1266738 Developmental Biology 2
Partners
CASP8FADDMALT1RIPK1TNFRSF25TNFRSF6BTRADDTRAF2

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 TL1A (TNFSF15) is a ligand for death receptor DR3 and decoy receptor TR6/DcR3. Binding to DR3 on T cells induces NF-κB activation and apoptosis in DR3-expressing cell lines, and costimulates T cells to increase IL-2 responsiveness and proinflammatory cytokine secretion. TR6-Fc antagonizes these signaling events. Receptor-ligand binding assays, NF-κB reporter assays, apoptosis assays, T cell functional assays in vitro and in vivo Immunity High 11911831
2003 TL1A-DR3 interaction in TF-1 cells induces formation of a signaling complex containing TRADD, TRAF2, and RIP, and activates NF-κB and ERK/JNK/p38 MAPK pathways. NF-κB activation prevents DR3-mediated apoptosis via upregulation of c-IAP2; siRNA knockdown of c-IAP2 sensitizes cells to TL1A-induced apoptosis. Co-immunoprecipitation of signaling complex, NF-κB reporter assays, MAPK inhibitor studies, RNA interference, apoptosis assays The Journal of biological chemistry High 12882979
2004 TL1A synergizes with IL-12 and IL-18 to augment IFN-γ production in human peripheral blood T cells and NK cells. DR3 expression is differentially regulated by IL-12/IL-18 in T cells versus NK cells. Cytokine stimulation assays, intracellular cytokine staining, agonistic anti-DR3 mAb experiments, flow cytometry for DR3 expression Journal of immunology High 15153521
2004 DcR3 (decoy receptor 3) induces angiogenesis in endothelial cells by neutralizing TL1A, which itself has angiostatic action on endothelial cells expressing DR3. Anti-TL1A and anti-DR3 antibodies mimic DcR3 pro-angiogenic effects, and TL1A promotes HUVEC apoptosis. Endothelial cell proliferation, migration, and tube formation assays; in vivo neovascularization; neutralizing antibody experiments Cancer research High 14871847
2007 TL1A expression in human monocytes and monocyte-derived dendritic cells is strongly induced by FcγR stimulation (immune complexes), but not by TLR agonists. FcγR-induced TL1A appears on the cell surface and in culture medium and enhances T cell responses. TLR and FcγR agonist stimulation, TL1A mRNA and protein detection, surface flow cytometry, T cell co-culture assays Journal of immunology High 17371957
2008 TL1A-DR3 interaction promotes proliferation and cytokine production from effector Th17 cells. TL1A-deficient dendritic cells have reduced capacity to support Th17 differentiation and proliferation, and TL1A-/- animals display decreased clinical severity in EAE. TL1A knockout mouse generation, EAE model, Th17 differentiation assays, DR3 expression profiling on Th17 cells The Journal of experimental medicine High 18411337
2008 TL1A upregulates both IFN-γ from Th1 cells and IL-17 from Th17 cells in gut-associated lymphoid tissue CD4+ T cells, synergistically with IL-12 and IL-23 respectively. Anti-TL1A antibody prevents and attenuates chronic DSS colitis. DSS chronic colitis model, cytokine measurement, anti-TL1A neutralizing antibody treatment, T-cell transfer colitis model Gastroenterology High 18598698
2009 Crystal structure of the human TL1A extracellular domain at 2.5 Å resolution reveals a jelly-roll fold typical of the TNF superfamily. Mutagenesis and biochemical characterization define the binding interface with DcR3 and DR3, showing that TL1A-DcR3 interaction differs from other characterized TNF ligand/receptor complexes. X-ray crystallography, mutagenesis, biochemical binding assays Biochemistry High 19522538
2009 VEGI/TNFSF15 inhibits differentiation of endothelial progenitor cells (EPCs) from bone marrow Sca1+ cells. VEGI induces apoptosis of differentiated EPCs but not early-stage EPCs; this is mediated by DR3, which is expressed only on differentiated EPCs. Neutralizing antibodies to DR3 inhibit VEGI-induced apoptosis. EPC differentiation assays, flow cytometry for endothelial markers, apoptosis assays, DR3 neutralizing antibody experiments Blood High 19329781
2009 Multiple bacterial species (gram-negative, gram-positive, anaerobes) induce TL1A expression in human APCs (monocytes and DCs) via the TLR signaling pathway; this induction is inhibited by downstream blockade of p38 MAPK and NF-κB activation. Bacterially induced TL1A augments IFN-γ production by CD4+ T cells. Bacterial stimulation of human monocytes/DCs, TL1A mRNA and protein measurement, kinase inhibitor studies, T cell co-culture European journal of immunology High 19839006
2010 TL1A drives IL-13-dependent small intestinal inflammation when constitutively expressed in T cells or dendritic cells in transgenic mice. TL1A-DR3 interactions are necessary and sufficient for T cell-dependent IBD, and TL1A suppresses inducible Treg generation. Transgenic mouse generation (T cell and DC-specific TL1A expression), TNBS colitis model with TL1A-DR3 blockade, cytokine and histological analysis Mucosal immunology High 20980995
2010 In naive human CD4+ T cells, TL1A via DR3 inhibits Th17 generation, while in committed Th17 cells it supports maintenance of IL-17A expression and proliferation under suboptimal TCR activation. DR3 is induced rapidly upon T cell activation and expressed prominently on IL-17-secreting T cells. Flow cytometry for DR3, Th17 differentiation assays, neutralizing antibodies, DR3-deficient mouse T cells, cytokine measurement FASEB journal High 20826539
2010 Membrane-bound TL1A (TL1A-M) can bind DR3 through cell-cell contact and induce IFN-γ secretion from IL-12/IL-18-primed CD4+ T cells, demonstrating functional activity of the membrane form distinct from soluble TL1A. TL1A-M expression in HEK-293 cells, DR3-Fc binding assay, T cell co-culture with IFN-γ measurement, anti-TL1A antibody blocking FEBS letters Medium 20403353
2011 AMPK activation upregulates LITAF transcription, and LITAF in turn drives TNFSF15 (TL1A) expression by binding to a specific promoter sequence. TNFSF15 inhibits proliferation of prostate cancer cells and endothelial cells, and intratumoral injection reduces tumor size and blood vessel number in vivo. shRNA knockdown, dominant-negative AMPK mutant, promoter binding assay, cell proliferation assays, xenograft tumor model Oncogene Medium 21217782
2013 TL1A drives allergic pathology through group 2 innate lymphoid cells (ILC2s), which express surface DR3 and produce IL-13 and type 2 cytokines in response to TL1A. DR3 is required for ILC2 expansion in T cell-dependent and -independent allergic disease models, independent of IL-25 or IL-33. Constitutive TL1A transgenic mice, DR3-deficient mice, ILC2 isolation and functional assays, allergic lung disease models Mucosal immunology High 24368564
2013 Soluble TL1A-Ig fusion protein mediates rapid in vivo expansion of FoxP3+ regulatory T cells (Tregs) to 30-35% of all CD4+ T cells. Treg expansion requires TCR engagement with MHC class II and is protective against allergic lung inflammation. TL1A-Ig also blocks de novo inducible Treg generation and attenuates Treg suppressive function. TL1A-Ig fusion protein generation, in vivo Treg expansion, TCR-MHC blockade experiments, allergic lung inflammation model Journal of immunology High 23319737
2013 TL1A signaling via DR3 on primary intestinal myofibroblasts directly increases collagen and IL-31Ra expression. Neutralizing TL1A antibody or DR3 deletion reduces fibroblast and myofibroblast numbers and reverses established colonic fibrosis. Primary myofibroblast culture, TL1A stimulation, anti-TL1A neutralizing antibody, DR3 knockout mice, collagen quantification Mucosal immunology High 24850426
2013 TL1A inhibits proliferation of activated human B cells that express DR3 following BCR polyclonal stimulation, without affecting B-cell survival. B cell DR3 expression by flow cytometry and immunofluorescence, B cell proliferation assays with TL1A treatment PloS one Medium 23565196
2013 TNFRSF25 (DR3) ligation by TL1A recruits TRAF2 and TRADD in primary T cells and activates NF-κB and PI3K/Akt pathways in a TCR- and IL-2R-dependent manner, leading to constitutive proliferation of CD4+FoxP3+ Tregs through tonic self-antigen exposure. Primary T cell signaling studies, pathway inhibitor assays, Treg proliferation assays Immunologic research Medium 24242819
2013 TL1A KO mice have ameliorated collagen-induced arthritis with reduced anti-collagen antibody titers. Plasma cells (but not B cells) express high levels of DR3 and are direct targets of TL1A; TL1A promotes plasma cell survival and antibody production. TL1A KO mouse generation, CIA model, serum antibody ELISA, DR3 expression on plasma cells by flow cytometry, plasma cell survival assays Journal of immunology High 24140642
2014 TNFSF15:DR3 interactions in human macrophages amplify PRR-induced MAPK/NF-κB/PI3K signaling and cytokine secretion. TACE-induced cleavage of membrane TNFSF15 produces soluble TNFSF15, which then drives TRADD/FADD/MALT-1- and caspase-8-mediated autocrine IL-1 secretion. The rs6478108 disease-risk allele increases TNFSF15 expression, leading to a gain-of-function in PRR signaling. Human macrophage stimulation, TACE inhibitors, caspase-8 inhibitors, siRNA knockdown, TRADD/FADD pathway analysis, risk allele genotyping Proceedings of the National Academy of Sciences of the United States of America High 25197060
2014 DR3 mediates TNFSF15-induced apoptosis in endothelial cells; DR3 siRNA knockdown confers resistance to TNFSF15-induced apoptosis and is associated with increased ERK1/2 MAPK activity and upregulation of anti-apoptotic c-FLIP and Bcl-2. TNFα-induced upregulation of TNFSF15 is partly responsible for TNFα-induced endothelial cell apoptosis. siRNA knockdown of DR3, apoptosis assays, western blot for c-FLIP and Bcl-2, ERK1/2 activity measurement, TNFSF15 neutralizing antibody The international journal of biochemistry & cell biology High 25161149
2015 Soluble TL1A trimers are sufficient to strongly activate DR3-associated pro- and anti-apoptotic signaling pathways without secondary ligand oligomerization, unlike TRAIL death receptors. TL1A-DR3 interaction affinity was measured in a cell-based system, and TL1A induces DR3 internalization. Recombinant soluble TL1A production, cell-based affinity measurement, DR3 signaling assays, receptor internalization assays The FEBS journal High 26509650
2015 The PBC-susceptibility allele at rs4979462 in the TNFSF15 locus generates a novel NF-1 binding site that enhances TNFSF15 promoter activity and increases endogenous TNFSF15 protein and mRNA expression. Luciferase reporter assay, electrophoretic mobility shift assay (EMSA), super-shift assay, endogenous mRNA/protein quantification by genotype Human genetics High 25899471
2013 TNFSF15 inhibits vasculogenesis by simultaneously promoting ubiquitin-mediated degradation of membrane VEGFR1 (mFlt1) and upregulating soluble VEGFR1 (sFlt1) in EPCs, disrupting VEGF/PlGF-induced eNOS and MAPK p38 activation. TNFSF15 also promotes alternative Flt1 pre-mRNA splicing toward sFlt1 by downregulating Jmjd6. EPC culture assays, Matrigel implant in vivo model, siRNA for DR3, Akt/ubiquitin pathway analysis, splicing factor (Jmjd6) knockdown Proceedings of the National Academy of Sciences of the United States of America High 23918400
2016 TNFSF15 suppresses VEGF production in endothelial cells by activating the JNK signaling pathway and transcription factor GATA3, which upregulates miR-29b that targets the 3'-UTR of VEGF transcript. siRNA against DR3 or neutralizing antibody against TNFSF15 inhibits miR-29b expression and restores VEGF production. siRNA knockdown, JNK inhibitor (SP600125), miR-29b measurement, 3'-UTR reporter assays, GATA3 siRNA Oncotarget High 27589684
2017 HDX-MS combined with computational modeling revealed that an anti-TL1A monoclonal antibody (mAb1) binds a discontinuous epitope on TL1A spanning the predicted TL1A-DR3 interaction interface, including residue R32 critical for DR3 but not DcR3 binding. Hydrogen/deuterium exchange mass spectrometry, electron-transfer dissociation MS, SASA analysis, computational modeling mAbs High 29135326
2018 Anti-TL1A antibody C03V binds the TL1A epitope encompassing residue R32, which is critical for TL1A-DR3 but not TL1A-DcR3 binding, explaining why it inhibits TL1A-DR3 interaction more potently than TL1A-DcR3 interaction. Antibody binding assays, DR3/DcR3 competitive binding assays, epitope mapping, in vitro potency assays, colitis and asthma mouse models mAbs High 29436901
2018 Antimitotic chemotherapeutic agents (taxol, vinblastine) induce lysosome-dependent secretion of TL1A, which engages DR3 to stimulate formation of a FADD- and caspase-8-containing DISC, activating apoptosis. DR3 and TL1A expression levels correlate with apoptotic response to antimitotic drugs in tumor xenografts. Cell death assays with spindle poisons, lysosomal secretion pathway analysis, DISC complex pull-down, DR3 KO cell lines, xenograft models Cell research High 29497138
2020 Autocrine/paracrine TNFSF15:DR3 interactions in human macrophages promote antimicrobial pathways including pyruvate dehydrogenase kinase 1-dependent bacterial uptake, reactive oxygen species, NOS2, and autophagy. The TRAF2/RIP1/RIP3 pathway is required for NF-κB/MAPK activation and antimicrobial induction; the FADD/MALT-1/caspase-8 pathway is required for cytokine secretion but less prominent in bacterial clearance. siRNA knockdown, pathway inhibitors, bacterial uptake and clearance assays, flow cytometry, ELISA, genotype stratification of risk carriers Cellular and molecular gastroenterology and hepatology High 32827707
2020 Direct TL1A signaling via DR3 on collagen-expressing fibroblasts (Col1a2+ cells) promotes intestinal fibrosis in vivo. RNA-sequencing of TL1A-stimulated fibroblasts identified Rho signal transduction as a major downstream pathway; Rho pathway inhibition attenuates TL1A-mediated fibroblast migration and activation. Rag-/- Dr3∆Col1a2 conditional KO mice, T cell transfer colitis, collagen deposition measurement, RNA-sequencing, Rho pathway inhibition Scientific reports High 33097818
2010 Two isoforms of TL1A with distinct functional activities are generated by differential ectodomain shedding: TL1A(L72-L251) promotes T cell activation, while a novel shorter fragment TL1A(V84-L251) induces growth arrest and apoptosis in endothelial cells. TL1A overexpression induces premature senescence in endothelial progenitor cells. TL1A isoform characterization in HUVECs and EPCs, overexpression experiments, senescence assays, apoptosis assays The journals of gerontology Medium 20675618
2024 TL1A is constitutively expressed in alveolar epithelial cells (basal cells) and acts as an epithelial alarmin that cooperates synergistically with IL-33 to induce a transient IL-9high GATA3low 'ILC9' phenotype in lung ILC2s, driving IL-5-dependent allergic airway inflammation. Large-scale proteomics, lung intravital microscopy, adoptive ILC9 transfer, mouse allergic airway models, human airway biopsy analysis The Journal of experimental medicine High 38597952
2009 TLR8 (or TLR7/8) activation potently inhibits FcγR/immune complex-induced TL1A expression in monocytes in a dose-dependent manner, resulting in inhibition of IFN-γ production by co-cultured CD4+ T cells. This suppression is independent of IFN-α. TLR ligand stimulation, TL1A mRNA and protein measurement, T cell co-culture IFN-γ assay, IFN-α neutralization European journal of immunology Medium 19637197

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 TL1A is a TNF-like ligand for DR3 and TR6/DcR3 and functions as a T cell costimulator. Immunity 523 11911831
2005 Single nucleotide polymorphisms in TNFSF15 confer susceptibility to Crohn's disease. Human molecular genetics 376 16221758
2003 Expression, localization, and functional activity of TL1A, a novel Th1-polarizing cytokine in inflammatory bowel disease. Journal of immunology (Baltimore, Md. : 1950) 258 14568967
2008 TL1A (TNFSF15) regulates the development of chronic colitis by modulating both T-helper 1 and T-helper 17 activation. Gastroenterology 214 18598698
2012 Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in the Japanese population. American journal of human genetics 213 23000144
2008 TL1A-DR3 interaction regulates Th17 cell function and Th17-mediated autoimmune disease. The Journal of experimental medicine 187 18411337
2006 Role of TL1A and its receptor DR3 in two models of chronic murine ileitis. Proceedings of the National Academy of Sciences of the United States of America 137 16698931
2007 The T cell costimulator TL1A is induced by FcgammaR signaling in human monocytes and dendritic cells. Journal of immunology (Baltimore, Md. : 1950) 129 17371957
2012 Identifying and testing candidate genetic polymorphisms in the irritable bowel syndrome (IBS): association with TNFSF15 and TNFα. Gut 127 22684480
2013 The TNF-family cytokine TL1A promotes allergic immunopathology through group 2 innate lymphoid cells. Mucosal immunology 126 24368564
2004 TL1A synergizes with IL-12 and IL-18 to enhance IFN-gamma production in human T cells and NK cells. Journal of immunology (Baltimore, Md. : 1950) 123 15153521
2010 The TNF-family cytokine TL1A drives IL-13-dependent small intestinal inflammation. Mucosal immunology 122 20980995
2003 TL1A-induced NF-kappaB activation and c-IAP2 production prevent DR3-mediated apoptosis in TF-1 cells. The Journal of biological chemistry 105 12882979
2004 Soluble decoy receptor 3 induces angiogenesis by neutralization of TL1A, a cytokine belonging to tumor necrosis factor superfamily and exhibiting angiostatic action. Cancer research 96 14871847
2008 Circulating levels of TNF-like cytokine 1A (TL1A) and its decoy receptor 3 (DcR3) in rheumatoid arthritis. Clinical immunology (Orlando, Fla.) 95 18757243
2011 Association of TNFSF15 polymorphism with irritable bowel syndrome. Gut 94 21636646
2019 TL1A (TNFSF15) and DR3 (TNFRSF25): A Co-stimulatory System of Cytokines With Diverse Functions in Gut Mucosal Immunity. Frontiers in immunology 92 30972074
2018 Inflammation-independent TL1A-mediated intestinal fibrosis is dependent on the gut microbiome. Mucosal immunology 89 29988118
2014 Inhibition of a novel fibrogenic factor Tl1a reverses established colonic fibrosis. Mucosal immunology 89 24850426
2007 TNFSF15 is an ethnic-specific IBD gene. Inflammatory bowel diseases 80 17663424
2021 Anti-TL1A Antibody PF-06480605 Safety and Efficacy for Ulcerative Colitis: A Phase 2a Single-Arm Study. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 78 34126262
2008 Association of TNFSF15 with Crohn's disease in Koreans. The American journal of gastroenterology 78 18422820
2015 VEGI attenuates the inflammatory injury and disruption of blood-brain barrier partly by suppressing the TLR4/NF-κB signaling pathway in experimental traumatic brain injury. Brain research 76 26080076
2009 Microbial induction of inflammatory bowel disease associated gene TL1A (TNFSF15) in antigen presenting cells. European journal of immunology 75 19839006
1999 Inhibition of angiogenesis and breast cancer xenograft tumor growth by VEGI, a novel cytokine of the TNF superfamily. International journal of cancer 75 10360832
2005 Involvement of TL1A and DR3 in induction of pro-inflammatory cytokines and matrix metalloproteinase-9 in atherogenesis. Cytokine 71 15760679
2011 Correction of the consequences of mitochondrial 3243A>G mutation in the MT-TL1 gene causing the MELAS syndrome by tRNA import into mitochondria. Nucleic acids research 65 21724600
2008 TL1A both promotes and protects from renal inflammation and injury. Journal of the American Society of Nephrology : JASN 65 18287561
2011 LITAF and TNFSF15, two downstream targets of AMPK, exert inhibitory effects on tumor growth. Oncogene 64 21217782
2015 The TNF-family cytokine TL1A: from lymphocyte costimulator to disease co-conspirator. Journal of leukocyte biology 61 26188076
2014 A TNFSF15 disease-risk polymorphism increases pattern-recognition receptor-induced signaling through caspase-8-induced IL-1. Proceedings of the National Academy of Sciences of the United States of America 61 25197060
2008 Contribution of TNFSF15 gene variants to Crohn's disease susceptibility confirmed in UK population. Inflammatory bowel diseases 61 18338776
2005 VEGI-192, a new isoform of TNFSF15, specifically eliminates tumor vascular endothelial cells and suppresses tumor growth. Clinical cancer research : an official journal of the American Association for Cancer Research 60 16061878
2014 The TNFSF15 gene single nucleotide polymorphism rs7848647 is associated with surgical diverticulitis. Annals of surgery 59 24814505
2013 The role of TL1A and DR3 in autoimmune and inflammatory diseases. Mediators of inflammation 59 24453414
2022 Role of TL1A in Inflammatory Autoimmune Diseases: A Comprehensive Review. Frontiers in immunology 58 35911746
2009 Inhibition of endothelial progenitor cell differentiation by VEGI. Blood 56 19329781
2020 The Role of the TL1A/DR3 Axis in the Activation of Group 2 Innate Lymphoid Cells in Subjects with Eosinophilic Asthma. American journal of respiratory and critical care medicine 53 32584596
2013 TNFSF15 inhibits vasculogenesis by regulating relative levels of membrane-bound and soluble isoforms of VEGF receptor 1. Proceedings of the National Academy of Sciences of the United States of America 47 23918400
2012 TNFSF15 Modulates Neovascularization and Inflammation. Cancer microenvironment : official journal of the International Cancer Microenvironment Society 47 22833050
2020 Common risk variants in NPHS1 and TNFSF15 are associated with childhood steroid-sensitive nephrotic syndrome. Kidney international 46 32554042
2010 Naive and activated T cells display differential responsiveness to TL1A that affects Th17 generation, maintenance, and proliferation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 46 20826539
1981 Antitermination and termination functions of the cloned nutL, N, and tL1 modules of coliphage lambda. Gene 46 6211393
2011 Down-modulation of TNFSF15 in ovarian cancer by VEGF and MCP-1 is a pre-requisite for tumor neovascularization. Angiogenesis 45 22210436
2018 An anti-TL1A antibody for the treatment of asthma and inflammatory bowel disease. mAbs 44 29436901
2009 Comprehensive linkage and association analyses identify haplotype, near to the TNFSF15 gene, significantly associated with spondyloarthritis. PLoS genetics 44 19543369
2009 VEGI-armed oncolytic adenovirus inhibits tumor neovascularization and directly induces mitochondria-mediated cancer cell apoptosis. Cell research 44 19918267
2017 Exome-wide association study reveals novel psoriasis susceptibility locus at TNFSF15 and rare protective alleles in genes contributing to type I IFN signalling. Human molecular genetics 42 28973304
2017 Hydrogen/deuterium exchange mass spectrometry and computational modeling reveal a discontinuous epitope of an antibody/TL1A Interaction. mAbs 42 29135326
2013 Cloning, expression, and functional characterization of TL1A-Ig. Journal of immunology (Baltimore, Md. : 1950) 42 23319737
2015 The TL1A/DR3/DcR3 pathway in autoimmune rheumatic diseases. Seminars in arthritis and rheumatism 39 25887448
2013 SUSTAINED TL1A (TNFSF15) EXPRESSION ON BOTH LYMPHOID AND MYELOID CELLS LEADS TO MILD SPONTANEOUS INTESTINAL INFLAMMATION AND FIBROSIS. European journal of microbiology & immunology 39 23638306
2021 Effect and Mechanism of TL1A Expression on Epithelial-Mesenchymal Transition during Chronic Colitis-Related Intestinal Fibrosis. Mediators of inflammation 36 34257516
2013 The TNF-family cytokine TL1A inhibits proliferation of human activated B cells. PloS one 35 23565196
2013 Immunobiology of TNFSF15 and TNFRSF25. Immunologic research 35 24242819
2010 Vascular endothelial growth inhibitor (VEGI; TNFSF15) inhibits bone marrow-derived endothelial progenitor cell incorporation into Lewis lung carcinoma tumors. Angiogenesis 34 21188501
2025 Targeting TL1A and DR3: the new frontier of anti-cytokine therapy in IBD. Gut 33 39266053
2020 TL1A Promotes Lung Tissue Fibrosis and Airway Remodeling. Journal of immunology (Baltimore, Md. : 1950) 33 32958689
2009 Biochemical and structural characterization of the human TL1A ectodomain. Biochemistry 33 19522538
2020 Direct signaling of TL1A-DR3 on fibroblasts induces intestinal fibrosis in vivo. Scientific reports 31 33097818
2018 Anti-mitotic chemotherapeutics promote apoptosis through TL1A-activated death receptor 3 in cancer cells. Cell research 31 29497138
2019 Effects and Mechanism of Constitutive TL1A Expression on Intestinal Mucosal Barrier in DSS-Induced Colitis. Digestive diseases and sciences 30 30949903
2010 TL1A selectively enhances IL-12/IL-18-induced NK cell cytotoxicity against NK-resistant tumor targets. Journal of clinical immunology 29 20349123
2016 TNFSF15 suppresses VEGF production in endothelial cells by stimulating miR-29b expression via activation of JNK-GATA3 signals. Oncotarget 28 27589684
2015 Soluble TL1A is sufficient for activation of death receptor 3. The FEBS journal 28 26509650
2014 TL1A regulates TCRγδ+ intraepithelial lymphocytes and gut microbial composition. European journal of immunology 28 25404161
2007 Functional characterization of tumor necrosis factor superfamily 15 (TNFSF15) induced by lipopolysaccharides and Eimeria infection. Developmental and comparative immunology 28 17349692
2005 Molecular cloning and functional characterizations of chicken TL1A. Developmental and comparative immunology 28 15896842
2015 Human primary biliary cirrhosis-susceptible allele of rs4979462 enhances TNFSF15 expression by binding NF-1. Human genetics 26 25899471
2013 TNF-like ligand 1A (TL1A) gene knockout leads to ameliorated collagen-induced arthritis in mice: implication of TL1A in humoral immune responses. Journal of immunology (Baltimore, Md. : 1950) 26 24140642
2008 Role of chicken TL1A on inflammatory responses and partial characterization of its receptor. Journal of immunology (Baltimore, Md. : 1950) 26 18523299
2009 TLR8-mediated activation of human monocytes inhibits TL1A expression. European journal of immunology 25 19637197
2024 TL1A is an epithelial alarmin that cooperates with IL-33 for initiation of allergic airway inflammation. The Journal of experimental medicine 24 38597952
2015 TL1A as a Potential Local Inducer of IL17A Expression in Colon Mucosa of Inflammatory Bowel Disease Patients. Scandinavian journal of immunology 24 26072972
2024 TL1A inhibition for inflammatory bowel disease treatment: From inflammation to fibrosis. Med (New York, N.Y.) 23 38574740
2014 Detection rates and phenotypic spectrum of m.3243A>G in the MT-TL1 gene: a molecular diagnostic laboratory perspective. Mitochondrion 23 24846800
2014 Death receptor 3 mediates TNFSF15- and TNFα-induced endothelial cell apoptosis. The international journal of biochemistry & cell biology 22 25161149
2010 Two functionally distinct isoforms of TL1A (TNFSF15) generated by differential ectodomain shedding. The journals of gerontology. Series A, Biological sciences and medical sciences 22 20675618
2009 Therapeutic Potential of VEGI/TL1A in Autoimmunity and Cancer. Advances in experimental medicine and biology 22 19760077
2020 A TRAIL-TL1A Paracrine Network Involving Adipocytes, Macrophages, and Lymphocytes Induces Adipose Tissue Dysfunction Downstream of E2F1 in Human Obesity. Diabetes 21 32732304
2020 TNFSF15 Promotes Antimicrobial Pathways in Human Macrophages and These Are Modulated by TNFSF15 Disease-Risk Variants. Cellular and molecular gastroenterology and hepatology 21 32827707
2017 Age-Dependent Association of TNFSF15/TNFSF8 Variants and Leprosy Type 1 Reaction. Frontiers in immunology 21 28261213
2011 CD161 DEFINES EFFECTOR T CELLS THAT EXPRESS LIGHT AND RESPOND TO TL1A-DR3 SIGNALING. European journal of microbiology & immunology 20 22348196
2006 Vascular endothelial growth inhibitor (VEGI), an endogenous negative regulator of angiogenesis. Seminars in ophthalmology 20 16517446
2022 The TL1A-DR3 Axis in Asthma: Membrane-Bound and Secreted TL1A Co-Determined the Development of Airway Remodeling. Allergy, asthma & immunology research 19 35255540
2019 Activation of the DR3-TL1A Axis in Donor Mice Leads to Regulatory T Cell Expansion and Activation With Reduction in Graft-Versus-Host Disease. Frontiers in immunology 19 31379829
2015 Association of Genetic Variations in TNFSF15 With Acute Anterior Uveitis in Chinese Han. Investigative ophthalmology & visual science 18 26200500
2014 Combining TNFSF15 and ASCA IgA can be used as a predictor for the stenosis/perforating phenotype of Crohn's disease. Journal of gastroenterology and hepatology 18 24783249
2013 Interferon-γ produced by tumor-infiltrating NK cells and CD4+ T cells downregulates TNFSF15 expression in vascular endothelial cells. Angiogenesis 18 24141405
2019 TL1A modulates the severity of colitis by promoting Th9 differentiation and IL-9 secretion. Life sciences 17 31176785
2016 Biologics beyond TNF-α inhibitors and the effect of targeting the homologues TL1A-DR3 pathway in chronic inflammatory disorders. Immunopharmacology and immunotoxicology 17 26810853
2012 Advancement in the research on vascular endothelial growth inhibitor (VEGI). Targeted oncology 17 22388993
2011 No association between TNFSF15 and IL23R with ulcerative colitis in Koreans. Journal of human genetics 17 21228792
2010 Functional signaling of membrane-bound TL1A induces IFN-gamma expression. FEBS letters 17 20403353
2021 Genome-wide association study identifies TNFSF15 associated with childhood asthma. Allergy 16 34022066
2016 Downregulation of VEGF and upregulation of TL1A expression induce HUVEC apoptosis in response to high glucose stimuli. Molecular medicine reports 16 26936681
2020 Circulating TNF-like protein 1A (TL1A) is elevated early in rheumatoid arthritis and depends on TNF. Arthritis research & therapy 15 32381123
2018 TL1A mediates fibroblast-like synoviocytes migration and Indian Hedgehog signaling pathway via TNFR2 in patients with rheumatoid arthritis. European cytokine network 15 29748156
2016 Fine-mapping analysis revealed complex pleiotropic effect and tissue-specific regulatory mechanism of TNFSF15 in primary biliary cholangitis, Crohn's disease and leprosy. Scientific reports 15 27507062
2014 TL1A induces TCR independent IL-6 and TNF-α production and growth of PLZF⁺ leukocytes. PloS one 15 24416448