Affinage

LTA

Lymphotoxin-alpha · UniProt P01374

Round 2 corrected
Length
205 aa
Mass
22.3 kDa
Annotated
2026-04-28
130 papers in source corpus 25 papers cited in narrative 25 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

LTA (lymphotoxin-alpha) is a TNF-family cytokine that functions both as a secreted homotrimer (LTα3) signaling through TNFR1/TNFR2 and HVEM, and as a membrane-anchored LTα1β2 heterotrimer signaling through the dedicated LTβR, thereby orchestrating lymphoid organ development, immune cell homeostasis, and inflammatory responses (PMID:8387891, PMID:8171323, PMID:9462508). Secreted LTα3 induces adhesion molecules (VCAM-1, ICAM-1, MAdCAM-1) and chemokines (RANTES, IP-10, MCP-1) on endothelial cells and exerts direct cytotoxicity against tumor cells, while the membrane-bound LTα1β2 complex engages LTβR to activate TRAF2/3/5-dependent NF-κB signaling (including alternative/RelB pathway), driving lymphoid organogenesis, dendritic cell recruitment, fibroblastic reticular cell maintenance, and intestinal goblet cell differentiation (PMID:9862717, PMID:12732657, PMID:12560241, PMID:32591396). A coding variant (Thr26Asn) that enhances VCAM-1 induction in vascular smooth-muscle cells, together with a galectin-2 interaction that modulates LTα secretion, links LTA to inflammatory cardiovascular disease including myocardial infarction (PMID:12426569, PMID:15129282). Triple knockout studies demonstrate that TNF, LTα, and LTβ have largely non-redundant roles in splenic microarchitecture, with LTα contributing uniquely to both innate and adaptive immune compartmentalization (PMID:12446781).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1984 High

    Establishing what LTA is: purification and cDNA cloning defined lymphotoxin as a ~20 kDa glycoprotein cytotoxin produced by lymphocytes, capable of killing tumor cells in vitro and in vivo.

    Evidence Biochemical purification from 1788 cells and recombinant expression in E. coli with cytotoxicity validation

    PMID:6334807 PMID:6608523

    Open questions at the time
    • Oligomeric state not yet established
    • Receptor identity unknown
    • In vivo physiological role beyond tumor cytotoxicity undefined
  2. 1985 High

    Resolving how LTA relates to TNF-α: radioligand competition showed both cytokines share a common receptor, and genomic mapping placed the two genes in tandem on chromosome 6 with significant exon homology, establishing them as paralogous ligands.

    Evidence 125I-TNF-α competitive displacement on ME-180 cells; genomic cloning and sequencing

    PMID:2995927 PMID:3001529

    Open questions at the time
    • Identity of receptor(s) at molecular level unknown
    • Whether LTA has receptor(s) distinct from TNF not resolved
  3. 1990 High

    Identifying the shared receptor: cloning of TNFR1 (p55) confirmed it binds both TNF-α and LTA, providing the molecular identity of the receptor mediating LTA's cytotoxic and inflammatory effects.

    Evidence Expression library screening with radiolabeled TNF-α, binding confirmation with LTA

    PMID:2160731

    Open questions at the time
    • Existence of LTA-specific receptors not excluded
    • Signaling mechanisms downstream of TNFR1 for LTA not defined
  4. 1992 High

    Structural basis of function: the 1.9 Å crystal structure revealed LTA forms a jellyroll β-sandwich homotrimer, and mutagenesis of Asp-50 and Tyr-108 at the intersubunit groove mapped the receptor-binding site, later confirmed by the 2.85 Å LTA–TNFR1 co-crystal showing three receptors engaging one trimer symmetrically.

    Evidence X-ray crystallography of free LTA and LTA–TNFR1 complex with site-directed mutagenesis

    PMID:1733919 PMID:8387891

    Open questions at the time
    • Structure of the LTα1β2 heteromer not determined
    • Conformational changes upon receptor engagement not characterized
  5. 1993 High

    Discovery of the membrane-bound heteromer: identification of LTβ as a type II transmembrane protein that forms LTα1β2 complexes on activated lymphocyte surfaces redefined LTA biology, showing it participates in two distinct ligand systems—secreted LTα3 and membrane-anchored LTα1β2.

    Evidence Cell surface biochemistry, cDNA cloning, and immunoprecipitation from activated T/B cells

    PMID:7916655

    Open questions at the time
    • Stoichiometry of heteromer (α1β2 vs α2β1) not fully resolved
    • Distinct downstream signaling not yet defined
  6. 1994 High

    A dedicated receptor for the heteromer: LTβR was identified as binding membrane LTα1β2 but not LTα3 or TNF, establishing that the two LTA-containing ligands engage entirely separate receptor pathways.

    Evidence Receptor binding assays and cDNA cloning with specificity determination

    PMID:8171323

    Open questions at the time
    • Downstream signaling cascades of LTβR not defined
    • In vivo biological consequences of LTβR engagement unknown
  7. 1998 High

    Defining the unique inflammatory outputs of each ligand form: LTα3 was shown to be the most potent inducer of MAdCAM-1 and to induce VCAM-1, ICAM-1, and chemokines on endothelial cells; separately, HVEM was identified as an additional LTα3 receptor distinct from TNFR1/2, and membrane anchoring (not ligand identity) was shown to be required for TNF receptor downmodulation, explaining why secreted LTα3 does not desensitize its own receptor.

    Evidence Recombinant LTα3 treatment of endothelial cells; receptor binding assays for HVEM; chimeric membrane-anchored LTα constructs in L929r2 cells

    PMID:9462508 PMID:9862717 PMID:9864375

    Open questions at the time
    • HVEM signaling downstream of LTα3 binding not characterized
    • Relative contribution of TNFR1 vs HVEM to LTα3 functions in vivo unknown
  8. 2000 Medium

    Epitope mapping on HVEM revealed that LTα3, LIGHT, and HSV gD bind to distinct non-overlapping sites, with conformational cross-talk between binding events, clarifying how multiple ligands share this receptor.

    Evidence Competitive binding with receptor peptides (BP-1, BP-2) and monoclonal antibodies

    PMID:11164894

    Open questions at the time
    • Structural basis of non-overlapping binding not determined at atomic level
    • Functional consequences of simultaneous ligand occupancy unknown
  9. 2002 High

    Genetic dissection of non-redundancy and disease relevance: triple TNF/LTα/LTβ KO mice showed that LTA has non-redundant functions in splenic microarchitecture; concurrently, the Thr26Asn coding variant was functionally linked to enhanced VCAM-1 induction and myocardial infarction risk, connecting LTA polymorphisms to human cardiovascular disease.

    Evidence Cre-loxP triple KO with histological analysis; large-scale SNP association (92,788 SNPs) with in vitro functional validation in coronary artery smooth-muscle cells

    PMID:12426569 PMID:12446781

    Open questions at the time
    • Causal role of LTA variant in MI not confirmed by Mendelian randomization or interventional study
    • Mechanism by which Thr26Asn increases VCAM-1 induction not structurally explained
  10. 2003 High

    Distinct roles of LTα3 vs LTα1β2 in lymphoid organogenesis and DC biology were delineated: LTα1β2 uniquely drives PNAd expression on HEV and T/B compartmentalization via LTβR, while LTα3 (via TNFR) independently supports DC maturation from BM progenitors, with LTα1β2–LTβR required for DC recruitment to peripheral lymphoid organs.

    Evidence RIP-LTα vs RIP-LTαβ transgenic mice with LTβ−/− controls; BM-derived DC cultures from triple KO mice with recombinant TNF rescue

    PMID:12560241 PMID:12732657

    Open questions at the time
    • Signals downstream of TNFR that support DC maturation not defined
    • Whether LTα3-HVEM contributes to DC biology not tested
  11. 2004 High

    Galectin-2 was identified as a direct LTα binding partner that modulates its secretion; a SNP reducing LGALS2 expression associated with MI risk, linking LTα's secretory regulation to atherosclerotic inflammation.

    Evidence Protein interaction assay, secretion assay, immunohistochemistry of human atherosclerotic lesions

    PMID:15129282

    Open questions at the time
    • Structural basis of galectin-2–LTα interaction not determined
    • Whether galectin-2 affects LTα3 vs LTα1β2 differentially is unknown
  12. 2007 Medium

    LTβR signaling through TRAF2/3/5 was established but shown to be incomplete: TRAF-KO mice do not fully phenocopy LTβR-pathway deficiency, indicating additional adaptors; separately, LTαβ–LTβR signaling was shown to regulate unconventional T cell development in thymus.

    Evidence Genetic epistasis of TRAF-KO vs LTβR-KO mice; thymocyte phenotyping in LTβR-deficient mice

    PMID:17336158 PMID:17633025

    Open questions at the time
    • Identity of non-TRAF LTβR adaptors unknown
    • Direct vs indirect effects of LTβR on thymic epithelium not resolved
  13. 2009 High

    Sustained hepatic LTαβ signaling through LTβR and IKKβ was causally linked to hepatocellular carcinoma in transgenic mice, with LTβR blockade suppressing tumor formation, establishing the oncogenic potential of chronic LT pathway activation.

    Evidence Liver-specific LTαβ transgenic mice with LTβR inhibition, IKKβ conditional KO, and lymphocyte depletion

    PMID:19800575

    Open questions at the time
    • Whether human HCC involves LTβR pathway activation not established
    • Specific NF-κB target genes mediating carcinogenesis not identified
  14. 2020 High

    ILC3-derived LT signaling through epithelial LTβR and the alternative NF-κB (RelB) pathway was shown to drive intestinal goblet cell differentiation and MUC2 expression during infection, defining a non-lymphoid organogenesis role for LT in mucosal barrier defense.

    Evidence ILC3-specific LT conditional KO, IEC-specific LTβR conditional KO, RelB signaling analysis during Listeria infection

    PMID:32591396

    Open questions at the time
    • Whether this mechanism operates in homeostatic (non-infectious) goblet cell renewal is unknown
    • Specific RelB target genes driving GC differentiation not identified

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the atomic structure of the LTα1β2–LTβR complex, the identity of non-TRAF adaptors downstream of LTβR, the in vivo relative contributions of TNFR1 vs HVEM to LTα3 functions, and whether therapeutic LTβR modulation can be exploited in human disease without disrupting lymphoid homeostasis.
  • No crystal structure of LTα1β2 heteromer or its receptor complex
  • Non-TRAF signaling adaptors for LTβR unidentified
  • HVEM vs TNFR1 contribution to LTα3 biology in vivo not dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 5 GO:0098772 molecular function regulator activity 2
Localization
GO:0005576 extracellular region 4 GO:0005886 plasma membrane 1
Pathway
R-HSA-168256 Immune System 5 R-HSA-162582 Signal Transduction 4 R-HSA-1266738 Developmental Biology 2 R-HSA-1643685 Disease 2
Partners
LGALS2LTBLTBRTNFRSF14TNFRSF1ATRAF2TRAF3TRAF5
Complex memberships
LTα1β2 heterotrimerLTα3 homotrimer

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1984 Human lymphotoxin (LTA) was purified to homogeneity from a lymphoblastoid cell line (1788 cells) and characterized as a glycoprotein with apparent molecular weight ~20,000 Da, isoelectric point of 5.8, and specific cytotoxic activity of ~40×10^6 units/mg against tumor cell lines in vitro and in vivo. Protein purification (DEAE-cellulose, isoelectric focusing, lentil lectin-Sepharose, PAGE), cytotoxicity assays The Journal of biological chemistry High 6608523
1984 A cDNA encoding human lymphotoxin (LTA) was cloned and expressed in E. coli; purified recombinant LTA showed cytotoxic activity on murine and human tumor cell lines in vitro and caused necrosis of murine sarcomas in vivo, establishing LTA as a functional cytotoxin. cDNA cloning, recombinant expression, cytotoxicity assay Nature High 6334807
1985 Human LTA (TNF-beta) and TNF-alpha share a common receptor on ME-180 cells; both cytokines compete for the same binding site (Kd ~0.2 nM, ~2,000 sites/cell), and IFN-gamma pre-treatment upregulates total TNF receptor number 2–3 fold without changing affinity. Radioligand binding assay with 125I-TNF-alpha, competitive displacement with unlabeled TNF-alpha and TNF-beta Nature High 3001529
1985 LTA and TNF genes are closely linked on human chromosome 6, each ~3 kb in length interrupted by three introns, with only their last exons (encoding >80% of secreted protein) significantly homologous (56%), providing the structural basis for their functional similarity. Genomic cloning, restriction mapping, sequencing, chromosomal localization Nucleic acids research High 2995927
1990 A 461-amino acid integral membrane protein (TNFR1/p55) was cloned from a human lung fibroblast library by expression screening with radiolabeled TNF-alpha; it binds both TNF-alpha and TNF-beta (LTA), defining the TNF receptor family with a cysteine-rich extracellular domain. cDNA expression library screening with radiolabeled ligand, binding assay Science High 2160731
1991 The NcoI RFLP in the first intron of the LTA (TNFB) gene results in an amino acid difference at position 26 (Asn in TNFB*1, Thr in TNFB*2); the TNFB*1 allele is associated with significantly higher TNF-beta protein and mRNA production following mitogen stimulation of PBMCs, demonstrating that this intronic polymorphism functionally regulates LTA transcription and/or protein levels. PCR-RFLP genotyping, ELISA, Northern blot, DNA sequencing The Journal of experimental medicine High 1670638
1992 The crystal structure of recombinant human lymphotoxin (LTA, residues 24–171) was determined at 1.9-Å resolution; LTA folds into a 'jellyroll' beta-sheet sandwich forming a homotrimer stabilized primarily by hydrophobic interactions, structurally similar to TNF-alpha. Two mutations (Asp-50 and Tyr-108) that abolish LTA cytotoxicity map to intersubunit loops at the base of the trimer, identifying the receptor-binding site. X-ray crystallography, site-directed mutagenesis, cytotoxicity assay The Journal of biological chemistry High 1733919
1993 The crystal structure of the soluble human 55-kDa TNFR1 complexed with LTA (TNF-beta) was determined at 2.85-Å resolution, revealing three receptor molecules bound symmetrically to one LTA trimer. The receptor binds in the groove between adjacent LTA subunits, defining the structural basis for TNF receptor activation. X-ray crystallography of receptor-ligand complex Cell High 8387891
1993 LTA (lymphotoxin-alpha) is present on the surface of activated T, B, and LAK cells as a heteromeric complex with a newly identified 33-kDa type II transmembrane glycoprotein called lymphotoxin-beta (LTβ), whose gene maps next to the TNF-LTA locus in the MHC; this cell-surface LTα–LTβ complex is distinct from secreted homotrimeric LTα3. Cell surface biochemistry, cDNA cloning, immunoprecipitation Cell High 7916655
1994 A receptor specific for the cell-surface LTα–LTβ complex (LTβR) was identified; this receptor does not bind secreted homotrimeric LTα3 or TNF, demonstrating that the membrane-bound LTαβ heteromer signals through a distinct receptor pathway. Receptor binding assays, cDNA cloning Science High 8171323
1998 LTA3 (secreted homotrimeric LTα) induces expression of adhesion molecules (VCAM, ICAM, E-selectin, MAdCAM-1) and chemokines (RANTES, IP-10, MCP-1) in murine endothelial cells and mediates cytotoxicity of WEHI target cells; mLTα3 was the most potent inducer of MAdCAM-1 among LTα, TNF-α forms tested, while none induced PNAd, establishing unique proinflammatory activities of homotrimeric LTα3. Recombinant cytokine treatment of endothelial cell line (bEnd.3), cytotoxicity assay, mRNA and protein expression analysis Journal of immunology High 9862717
1998 HVEM (herpesvirus entry mediator) binds two cellular TNF-family ligands: secreted LTα (LTA) and LIGHT. LIGHT also engages the LTβR but does not form complexes with LTα or LTβ. HSV gD inhibits HVEM–LIGHT interaction, and LIGHT and gD compete for HVEM-dependent HSV cell entry, identifying LTα as a natural ligand for HVEM. Receptor-ligand binding assays, viral entry inhibition assays, co-immunoprecipitation Immunity High 9462508
1998 Autocrine TNF (membrane-bound precursor) completely downmodulates expression of both p55 and p75 TNF receptors in L929r2 cells, conferring resistance to TNF/LTA cytotoxicity; autocrine LTα (secreted via classical pathway, not membrane-anchored) does not downmodulate receptors. Membrane retention of LTα (achieved by replacing its signal peptide with a membrane anchor) restored receptor downmodulation, demonstrating that membrane anchoring—not ligand identity—is required for TNF receptor downregulation. Stable transfection, flow cytometry for receptor expression, cytotoxicity assays, chimeric membrane-anchored LTα construct The Journal of cell biology High 9864375
2000 LTα3, LIGHT, and HSV gD each bind to distinct non-overlapping sites on HVEM; binding of one ligand to HVEM alters its conformation and affects interaction with the other ligands. Specifically, LTα and gD bind to different epitopes on HVEM defined by differential peptide inhibition (BP-1 vs BP-2) and monoclonal antibody mapping. Competitive binding assays with receptor peptides (BP-1, BP-2) and monoclonal antibodies, truncated receptor constructs Molecular immunology Medium 11164894
2002 TNF, LTα, and LTβ have largely non-redundant functions in vivo; triple knockout mice (TNF/LTα/LTβ-deficient) show a combination of individual knockout phenotypes plus severer disruption of splenic lymphoid microarchitecture (T/B cell positioning, compartmentalization) than any single KO alone, demonstrating that both TNF and LT pathways are independently required for normal splenic organization. Cre-loxP deletion of entire TNF/LT locus, histology, immunofluorescence, comparison with single KO mice Molecular and cellular biology High 12446781
2002 Two SNPs in LTA—one in intron 1 enhancing LTA transcription and one in the coding region changing Thr26Asn—form a risk haplotype for myocardial infarction. In vitro functional assays showed the Thr26Asn LTA variant caused a ~2-fold increase in induction of cell-adhesion molecules (VCAM1 and others) in human coronary artery smooth-muscle cells, implicating LTA as a functional mediator in MI pathogenesis. Large-scale SNP association study (92,788 SNPs), in vitro promoter transcription assay, cell-adhesion molecule induction assay in vascular smooth-muscle cells Nature genetics High 12426569
2003 Simultaneous expression of LTα and LTβ (LTαβ) in pancreatic islets (RIP-LTαβ transgenic mice) produced more extensive intra-islet lymphoid neogenesis than LTα alone, with distinct T/B cell compartmentalization, FDC networks, and prominent lymphoid chemokines (CCL21, CCL19, CXCL13). Critically, luminal PNAd expression on HEV required HEC-6ST sulfotransferase and was dependent on LTαβ signaling but not LTα3 alone, demonstrating that LTαβ (membrane-bound heteromer) and LTα3 (secreted homotrimer) have distinct roles in lymphoid organogenesis. Transgenic mouse models (RIP-LTα, RIP-LTαβ), LTβ−/− mice, immunohistochemistry, flow cytometry The Journal of experimental medicine High 12732657
2003 LTα (via TNFR) is required for in vitro development/maturation of dendritic cells from BM progenitors independently of LTβ/LTβR; conversely, LTαβ–LTβR signaling (not TNF–TNFR) is specifically required for efficient recruitment of mature DCs into peripheral lymphoid organs, demonstrating two mechanistically distinct contributions of LT cytokines to DC biology. BM-derived DC cultures from single and triple TNF/LT KO mice, GM-CSF/IL-4 stimulation, recombinant TNF rescue, blocking antibodies, in vivo DC enumeration Blood High 12560241
2004 LTα protein directly binds galectin-2 (encoded by LGALS2); a SNP in LGALS2 that reduces its transcriptional expression is associated with MI risk and in vitro leads to altered secretion of LTα from cells, linking the galectin-2–LTα interaction to the inflammatory pathogenesis of MI. Galectin-2 and LTα colocalize in smooth-muscle cells and macrophages in human atherosclerotic lesions. Protein interaction assay (LTA–galectin-2 binding), reporter transcription assay, case-control association, immunohistochemistry of human lesions Nature High 15129282
2007 The LTβR signaling pathway activates NF-κB gene transcription programs and cell death through TRAF-2, -3, and -5 adaptor proteins; however, TRAF-deficient mice do not fully phenocopy LTβR-pathway-deficient mice, indicating that LTβR can engage additional or alternative signaling mechanisms beyond TRAFs. Genetic analysis of TRAF-KO vs. LTβR-pathway-KO mouse phenotypes, signaling pathway analysis Advances in experimental medicine and biology Medium 17633025
2007 LTαβ–LTβR signaling plays a pivotal role in the ontogeny of unconventional T cells including γδ T cells and invariant NKT cells; double-positive thymocytes regulate differentiation of early thymocyte progenitors and γδ T cells through a mechanism dependent on LTβR, and LTβR signaling in thymic stroma affects central tolerance to peripherally restricted antigens. Analysis of LTβR-deficient mice, thymocyte subset phenotyping, thymic chimera experiments Trends in immunology Medium 17336158
2009 Liver-specific overexpression of LTα and LTβ in transgenic mice induces liver inflammation and hepatocellular carcinoma (HCC); HCC development depends on lymphocytes and hepatocyte IKKβ but is independent of TNFR1, and LTβR inhibition suppresses HCC formation, causally linking sustained hepatic LT signaling through LTβR/IKKβ to hepatitis-induced HCC. Liver-specific LTαβ transgenic mice, LTβR inhibition, IKKβ conditional KO, lymphocyte depletion, tumor histology Cancer cell High 19800575
2014 T lymphocytes maintain the structure and function of fibroblastic reticular cells (FRCs) in the spleen via LTβ; absence of T cells downregulates LTβ expression, causing structural FRC disorder and reduced CCL21/CCL19 chemokine expression and T cell homing. T cell reconstitution restores FRC structure only when LTβR is functional, establishing a T cell→LTβ→LTβR→FRC regulatory axis. Nude mouse model, T cell transfer, LTβR blockade, immunofluorescence microscopy, chemokine expression analysis BMC immunology Medium 25266629
2018 Teleost (fugu) LTβR binds LIGHT but not membrane TNFN (the teleost LT-like molecule), suggesting LIGHT was the original ligand for LTβR before acquisition of LTα/LTβ ligands in evolution. Fugu LTβR intracellular domain binds TRAF2 but not TRAF3, potentially enabling classical NF-κB signaling but not the alternative pathway, indicating the TRAF3-binding domain was acquired later to enable alternative NF-κB signaling. Recombinant protein binding assays, TRAF interaction assays, phylogenetic and sequence analysis Journal of immunology Medium 29769272
2020 ILC3-derived LT (but not LIGHT) signals through LTβR expressed on intestinal epithelial cells (IECs) to drive goblet cell (GC) differentiation and MUC2 expression during Listeria infection via the alternative NF-κB pathway (RelB); conditional LT KO in ILC3s or IEC-specific LTβR KO impaired GC differentiation-related gene expression and anti-Listeria defense without affecting IEC proliferation or cell death. Villin-Cre conditional LTβR KO, ILC3-specific LT conditional KO, single KO mice for LIGHT/LT, Ki-67/Annexin V staining, RelB signaling analysis Journal of immunology High 32591396

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nature genetics 2036 21102463
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
1985 Characterization of receptors for human tumour necrosis factor and their regulation by gamma-interferon. Nature 1055 3001529
1990 A receptor for tumor necrosis factor defines an unusual family of cellular and viral proteins. Science (New York, N.Y.) 1053 2160731
1993 Crystal structure of the soluble human 55 kd TNF receptor-human TNF beta complex: implications for TNF receptor activation. Cell 972 8387891
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2002 Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction. Nature genetics 723 12426569
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
1984 Cloning and expression of cDNA for human lymphotoxin, a lymphokine with tumour necrosis activity. Nature 673 6334807
1998 LIGHT, a new member of the TNF superfamily, and lymphotoxin alpha are ligands for herpesvirus entry mediator. Immunity 618 9462508
1991 Polymorphic structure of the tumor necrosis factor (TNF) locus: an NcoI polymorphism in the first intron of the human TNF-beta gene correlates with a variant amino acid in position 26 and a reduced level of TNF-beta production. The Journal of experimental medicine 506 1670638
1985 Human lymphotoxin and tumor necrosis factor genes: structure, homology and chromosomal localization. Nucleic acids research 506 2995927
2015 Widespread macromolecular interaction perturbations in human genetic disorders. Cell 454 25910212
1993 Lymphotoxin beta, a novel member of the TNF family that forms a heteromeric complex with lymphotoxin on the cell surface. Cell 444 7916655
1989 A tumor necrosis factor-binding protein purified to homogeneity from human urine protects cells from tumor necrosis factor toxicity. The Journal of biological chemistry 442 2545693
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
1994 A lymphotoxin-beta-specific receptor. Science (New York, N.Y.) 342 8171323
2009 A lymphotoxin-driven pathway to hepatocellular carcinoma. Cancer cell 329 19800575
2006 Genetic variation in TNF and IL10 and risk of non-Hodgkin lymphoma: a report from the InterLymph Consortium. The Lancet. Oncology 313 16389181
1984 Human lymphotoxin. Production by a lymphoblastoid cell line, purification, and initial characterization. The Journal of biological chemistry 300 6608523
1992 Effects of the human immunodeficiency virus type 1 Tat protein on the expression of inflammatory cytokines. Journal of virology 288 1279199
1991 NIT-1, a pancreatic beta-cell line established from a transgenic NOD/Lt mouse. Diabetes 243 1647994
2007 Genetic susceptibility to respiratory syncytial virus bronchiolitis is predominantly associated with innate immune genes. The Journal of infectious diseases 223 17703412
1998 Edible vaccine protects mice against Escherichia coli heat-labile enterotoxin (LT): potatoes expressing a synthetic LT-B gene. Vaccine 217 9682399
2003 Ectopic LT alpha beta directs lymphoid organ neogenesis with concomitant expression of peripheral node addressin and a HEV-restricted sulfotransferase. The Journal of experimental medicine 204 12732657
2004 Functional variation in LGALS2 confers risk of myocardial infarction and regulates lymphotoxin-alpha secretion in vitro. Nature 199 15129282
1992 The structure of human lymphotoxin (tumor necrosis factor-beta) at 1.9-A resolution. The Journal of biological chemistry 182 1733919
2010 Solution of the structure of the TNF-TNFR2 complex. Science signaling 179 21081755
2009 Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip. American journal of human genetics 164 19913121
2015 The Dlk1-Gtl2 Locus Preserves LT-HSC Function by Inhibiting the PI3K-mTOR Pathway to Restrict Mitochondrial Metabolism. Cell stem cell 154 26627594
2001 Septic shock and respiratory failure in community-acquired pneumonia have different TNF polymorphism associations. American journal of respiratory and critical care medicine 150 11401880
1997 ATAR, a novel tumor necrosis factor receptor family member, signals through TRAF2 and TRAF5. The Journal of biological chemistry 148 9153189
2003 Pneumococcal lipoteichoic acid (LTA) is not as potent as staphylococcal LTA in stimulating Toll-like receptor 2. Infection and immunity 143 14500472
2002 Frequency of cytokine polymorphisms in populations from western Europe, Africa, Asia, the Middle East and South America. Human immunology 139 12392859
2007 A Staphylococcus aureus ypfP mutant with strongly reduced lipoteichoic acid (LTA) content: LTA governs bacterial surface properties and autolysin activity. Molecular microbiology 118 17640274
2010 Tumor necrosis factor (TNF) and lymphotoxin-alpha (LTA) polymorphisms and risk of non-Hodgkin lymphoma in the InterLymph Consortium. American journal of epidemiology 109 20047977
1976 A reaction mechanism from steady state kinetic studies for O-acetylserine sulfhydrylase from Salmonella typhimurium LT-2. The Journal of biological chemistry 101 773932
1998 Lymphotoxin alpha3 induces chemokines and adhesion molecules: insight into the role of LT alpha in inflammation and lymphoid organ development. Journal of immunology (Baltimore, Md. : 1950) 98 9862717
2021 Relation of outcomes to ABC (Atrial Fibrillation Better Care) pathway adherent care in European patients with atrial fibrillation: an analysis from the ESC-EHRA EORP Atrial Fibrillation General Long-Term (AFGen LT) Registry. Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology 93 33006613
2002 CD4 T cells are the only lymphocytes needed to protect mice against rotavirus shedding after intranasal immunization with a chimeric VP6 protein and the adjuvant LT(R192G). Journal of virology 87 11752147
2008 Association between LTA, TNF and AGER polymorphisms and late diabetic complications. PloS one 76 18575614
2002 A functional antigen in a practical crop: LT-B producing maize protects mice against Escherichia coli heat labile enterotoxin (LT) and cholera toxin (CT). Transgenic research 76 12437079
2017 Extracellular Hsp70 induces inflammation and modulates LPS/LTA-stimulated inflammatory response in THP-1 cells. Cell stress & chaperones 67 29067554
1996 Crystal structure of a new heat-labile enterotoxin, LT-IIb. Structure (London, England : 1993) 67 8805549
1993 Polymorphism of the tumor necrosis factor beta gene in systemic lupus erythematosus: TNFB-MHC haplotypes. Immunogenetics 67 8436420
1999 Genetic polymorphisms at the tumour necrosis factor loci (TNFA and TNFB) in cardiac sarcoidosis. Tissue antigens 65 10488747
1997 Retardation or acceleration of diabetes in NOD/Lt mice mediated by intrathymic administration of candidate beta-cell antigens. Diabetes 63 9392483
2014 Differential localization of LTA synthesis proteins and their interaction with the cell division machinery in Staphylococcus aureus. Molecular microbiology 57 24533796
2003 Distinct contributions of TNF and LT cytokines to the development of dendritic cells in vitro and their recruitment in vivo. Blood 56 12560241
1991 Haplotypic polymorphisms of the TNFB gene. Immunogenetics 52 1671667
2006 Lipoteichoic acid (LTA) from Staphylococcus aureus stimulates human neutrophil cytokine release by a CD14-dependent, Toll-like-receptor-independent mechanism: Autocrine role of tumor necrosis factor-[alpha] in mediating LTA-induced interleukin-8 generation. Critical care medicine 50 16521278
2011 Endogenous MCP-1 promotes lung inflammation induced by LPS and LTA. Molecular immunology 49 21529952
2013 Antimicrobial peptide LL-37 attenuates LTA induced inflammatory effect in macrophages. International immunopharmacology 48 23375934
1988 Structure and expression of the ompB operon, the regulatory locus for the outer membrane porin regulon in Salmonella typhimurium LT-2. Journal of molecular biology 48 2845093
2002 Redundancy in tumor necrosis factor (TNF) and lymphotoxin (LT) signaling in vivo: mice with inactivation of the entire TNF/LT locus versus single-knockout mice. Molecular and cellular biology 46 12446781
2000 Comparative analysis of the mucosal adjuvanticity of the type II heat-labile enterotoxins LT-IIa and LT-IIb. Infection and immunity 46 10603399
2012 SNPs in PTGS2 and LTA predict pain and quality of life in long term lung cancer survivors. Lung cancer (Amsterdam, Netherlands) 45 22464751
1987 Ovulation and fertilization of primary and secondary oocytes in LT/Sv strain mice. Gamete research 45 3507361
2009 Effect of LTA isolated from bifidobacteria on D-galactose-induced aging. Experimental gerontology 41 19735715
2019 Bacillus pumilus SE5 originated PG and LTA tuned the intestinal TLRs/MyD88 signaling and microbiota in grouper (Epinephelus coioides). Fish & shellfish immunology 40 30849499
2010 Large-scale association analysis of TNF/LTA gene region polymorphisms in type 2 diabetes. BMC medical genetics 39 20459604
1996 Systemic lupus erythematosus with nephritis is strongly associated with the TNFB*2 homozygote in the Korean population. Human immunology 39 9157084
2005 Mucosal adjuvant properties of mutant LT-IIa and LT-IIb enterotoxins that exhibit altered ganglioside-binding activities. Infection and immunity 37 15731030
2012 Pandemic influenza A/H1N1 virus infection and TNF, LTA, IL1B, IL6, IL8, and CCL polymorphisms in Mexican population: a case-control study. BMC infectious diseases 36 23148654
2000 The three HveA receptor ligands, gD, LT-alpha and LIGHT bind to distinct sites on HveA. Molecular immunology 36 11164894
2015 Performances and Reliability of Bruker Microflex LT and VITEK MS MALDI-TOF Mass Spectrometry Systems for the Identification of Clinical Microorganisms. BioMed research international 35 26793718
2004 Haplotype structure of inflammatory cytokines genes (IL1B, IL6 and TNF/LTA) in US Caucasians and African Americans. Genes and immunity 33 15306845
1998 Cytostatic activity develops during meiosis I in oocytes of LT/Sv mice. Developmental biology 33 9705227
2016 Variants in LTA, TNF, IL1B and IL10 genes associated with the clinical course of sepsis. Immunologic research 32 27592234
1999 TNFA and TNFB polymorphisms in myasthenia gravis. Archives of neurology 32 10199335
2014 Lipoteichoic acid (LTA) and lipopolysaccharides (LPS) from periodontal pathogenic bacteria facilitate oncogenic herpesvirus infection within primary oral cells. PloS one 31 24971655
2013 Tumor necrosis factor B (TNFB) genetic variants and its increased expression are associated with vitiligo susceptibility. PloS one 31 24312346
2010 Extended LTA, TNF, LST1 and HLA gene haplotypes and their association with rubella vaccine-induced immunity. PloS one 31 20668555
2009 Investigation of TNFA 308G > A and TNFB 252G > A polymorphisms in genetic susceptibility to migraine. Journal of neurology 31 20035431
2007 The A subunit of type IIb enterotoxin (LT-IIb) suppresses the proinflammatory potential of the B subunit and its ability to recruit and interact with TLR2. Journal of immunology (Baltimore, Md. : 1950) 31 17404262
2009 TNF, LTA, HSPA1L and HLA-DR gene polymorphisms in HIV-positive patients with hypersensitivity to cotrimoxazole. Pharmacogenomics 30 19374512
2009 Enhanced fracture repair by leukotriene antagonism is characterized by increased chondrocyte proliferation and early bone formation: a novel role of the cysteinyl LT-1 receptor. Journal of cellular physiology 29 19544365
2024 Altered DNA methylation within DNMT3A, AHRR, LTA/TNF loci mediates the effect of smoking on inflammatory bowel disease. Nature communications 28 38238335
2018 Co-administered Tag-Less Toxoid Fusion 3xSTaN12S-mnLTR192G/L211A and CFA/I/II/IV MEFA (Multiepitope Fusion Antigen) Induce Neutralizing Antibodies to 7 Adhesins (CFA/I, CS1-CS6) and Both Enterotoxins (LT, STa) of Enterotoxigenic Escherichia coli (ETEC). Frontiers in microbiology 28 29922268
2007 The LT beta R signaling pathway. Advances in experimental medicine and biology 28 17633025
2021 Discovery of a Potent FLT3 Inhibitor (LT-850-166) with the Capacity of Overcoming a Variety of FLT3 Mutations. Journal of medicinal chemistry 27 34550682
2020 6-Gingerol exerts anti-inflammatory effects and protective properties on LTA-induced mastitis. Phytomedicine : international journal of phytotherapy and phytopharmacology 27 32531697
2016 Synthesis, docking, cytotoxicity, and LTA4H inhibitory activity of new gingerol derivatives as potential colorectal cancer therapy. Bioorganic & medicinal chemistry 27 28065501
2002 TNF alpha and LT alpha gene polymorphisms as additional markers of celiac disease susceptibility in a DQ2-positive population. Immunogenetics 27 12439617
2017 The development of novel LTA4H modulators to selectively target LTB4 generation. Scientific reports 26 28303931
2015 Modelling MS: Chronic-Relapsing EAE in the NOD/Lt Mouse Strain. Current topics in behavioral neurosciences 26 26126592
2003 Expression of lymphotoxin-beta (LT-beta) in chronic inflammatory conditions. The Journal of pathology 26 12474234
2019 20-Hydroxy- and 20-carboxy-leukotriene (LT) B4 downregulate LTB4 -mediated responses of human neutrophils and eosinophils. Journal of leukocyte biology 25 30676680
2019 NLRC5 negatively regulates LTA-induced inflammation via TLR2/NF-κB and participates in TLR2-mediated allergic airway inflammation. Journal of cellular physiology 25 30945291
2018 Induction of IL-10-balanced immune profiles following exposure to LTA from Staphylococcus epidermidis. Experimental dermatology 25 29569765
2002 Major histocompatibility complex class I chain related (MIC) A gene, TNFa microsatellite alleles and TNFB alleles in juvenile idiopathic arthritis patients from Latvia. Human immunology 25 11975986
1990 ras transfection and expression does not induce progression from tumorigenicity to metastatic ability in mouse LTA cells. Clinical & experimental metastasis 25 1697227
2020 The Synergism of PGN, LTA and LPS in Inducing Transcriptome Changes, Inflammatory Responses and a Decrease in Lactation as Well as the Associated Epigenetic Mechanisms in Bovine Mammary Epithelial Cells. Toxins 24 32545333
2019 Vps8 overexpression inhibits HOPS-dependent trafficking routes by outcompeting Vps41/Lt. eLife 24 31194677
2018 Significance of Enterotoxigenic Escherichia coli (ETEC) Heat-Labile Toxin (LT) Enzymatic Subunit Epitopes in LT Enterotoxicity and Immunogenicity. Applied and environmental microbiology 24 29802193
2007 Role of IL-6, TNF-A and LT-A variants in the modulation of the clinical expression of plaque-induced gingivitis. Journal of clinical periodontology 24 17953695
2000 Increased TNFA*2, but not TNFB*1, allele frequency in Spanish atopic patients. Journal of investigational allergology & clinical immunology 24 10923589
2017 Capturing LTA4 hydrolase in action: Insights to the chemistry and dynamics of chemotactic LTB4 synthesis. Proceedings of the National Academy of Sciences of the United States of America 22 28827365
2019 MyD88 hypermethylation mediated by DNMT1 is associated with LTA-induced inflammatory response in human odontoblast-like cells. Cell and tissue research 21 30707290
1997 Decreased tumour necrosis factor-beta production in TNFB*2 homozygote: an important predisposing factor of lupus nephritis in Koreans. Lupus 21 9302664
2023 Anti-inflammatory effects of chlorogenic acid from Taraxacum officinale on LTA-stimulated bovine mammary epithelial cells via the TLR2/NF-κB pathway. PloS one 19 36947494
2020 GtcA is required for LTA glycosylation in Listeria monocytogenes serovar 1/2a and Bacillus subtilis. Cell surface (Amsterdam, Netherlands) 19 32743150
2004 LTA 252G allele containing haplotype block is associated with high serum C-reactive protein levels. Atherosclerosis 19 15306179
2016 The chromosomal nature of LT-II enterotoxins solved: a lambdoid prophage encodes both LT-II and one of two novel pertussis-toxin-like toxin family members in type II enterotoxigenic Escherichia coli. Pathogens and disease 18 26755534
2015 Association between ANKK1 (rs1800497) and LTA (rs909253) Genetic Variants and Risk of Schizophrenia. BioMed research international 18 26114114
2014 T lymphocytes maintain structure and function of fibroblastic reticular cells via lymphotoxin (LT)-B. BMC immunology 18 25266629
2010 Diabetic retinopathy: Validation study of ALR2, RAGE, iNOS and TNFB gene variants in a south Indian cohort. Ophthalmic genetics 18 21067489
2007 The unconventional role of LT alpha beta in T cell differentiation. Trends in immunology 18 17336158
2022 Anti-Inflammatory Mechanism of An Alkaloid Rutaecarpine in LTA-Stimulated RAW 264.7 Cells: Pivotal Role on NF-κB and ERK/p38 Signaling Molecules. International journal of molecular sciences 17 35682568
2017 Inactivation of TNF/LT locus alters mouse metabolic response to concentrated ambient PM2.5. Toxicology 17 28917655
2012 A functional polymorphism of lymphotoxin-alpha (LTA) gene rs909253 is associated with gastric cancer risk in an Asian population. Cancer epidemiology 17 22748850
2021 Auraptene, a Monoterpene Coumarin, Inhibits LTA-Induced Inflammatory Mediators via Modulating NF-κB/MAPKs Signaling Pathways. Evidence-based complementary and alternative medicine : eCAM 16 34824589
2020 Type 3 Innate Lymphoid Cells Direct Goblet Cell Differentiation via the LT-LTβR Pathway during Listeria Infection. Journal of immunology (Baltimore, Md. : 1950) 16 32591396
2020 HEMA-induced oxidative stress inhibits NF-κB nuclear translocation and TNF release from LTA- and LPS-stimulated immunocompetent cells. Dental materials : official publication of the Academy of Dental Materials 15 33303231
2018 Staphylococcal LTA antagonizes the B cell-mitogenic potential of LPS. Scientific reports 15 29367683
2015 Response of Neutrophils to Extracellular Haemoglobin and LTA in Human Blood System. EBioMedicine 15 26137562
1995 TNFB gene polymorphism in patients with systemic lupus erythematosus in Korean. The Korean journal of internal medicine 15 7495771
2024 Processing of LtaS restricts LTA assembly and YSIRK preprotein trafficking into Staphylococcus aureus cross-walls. mBio 14 38174934
2017 Hispolon Suppresses LPS- or LTA-Induced iNOS/NO Production and Apoptosis in BV-2 Microglial Cells. The American journal of Chinese medicine 14 29121802
2016 The LT1 and LT2 variants of the enterotoxigenic Escherichia coli (ETEC) heat-labile toxin (LT) are associated with major ETEC lineages. Gut microbes 14 26939855
2010 Relationship between TNFA, TNFB and TNFRII gene polymorphisms and outcome after unrelated hematopoietic cell transplantation in a Chinese population. Bone marrow transplantation 14 20548340
2016 Immunogenic properties of trivalent recombinant protein composed of B-subunits of LT, STX-2, and CT toxins. Microbes and infection 13 26970204
2014 Association between TNF promoter -308 G>A and LTA 252 A>G polymorphisms and systemic lupus erythematosus. Molecular biology reports 13 24420856
2007 Effects of LT-K63 and CpG2006 on phenotype and function of murine neonatal lymphoid cells. Scandinavian journal of immunology 13 17850587
2001 The interaction of the polymorphisms in transporter of antigen peptides (TAP) and lymphotoxin alpha (LT-alpha) genes and atopic diseases in the Czech population. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 13 11591192
1998 Autocrine tumor necrosis factor (TNF) and lymphotoxin (LT) alpha differentially modulate cellular sensitivity to TNF/LT-alpha cytotoxicity in L929 cells. The Journal of cell biology 13 9864375
2018 Original Ligand for LTβR Is LIGHT: Insight into Evolution of the LT/LTβR System. Journal of immunology (Baltimore, Md. : 1950) 12 29769272
2008 Comparative analysis of the islet proteome between NOD/Lt and ALR/Lt mice. Annals of the New York Academy of Sciences 12 19120270
1990 Auranofin stimulates LTA hydrolase and inhibits 5-lipoxygenase/LTA synthase activity of isolated human neutrophils. Biochemical pharmacology 12 2157444