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Gene Review

LTA  -  lymphotoxin alpha

Homo sapiens

Synonyms: LT, LT-alpha, Lymphotoxin-alpha, TNF-beta, TNFB, ...
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Disease relevance of LTA


Psychiatry related information on LTA

  • Our results, which show for the first time strikingly increased CSF levels of TNF-alpha but not of TNF-beta, IL-1beta or IL-6 in AD and VAD, may form a conceptual framework for further studies of neuroprotective mechanisms in dementias [6].
  • We assessed the correlation between cognitive functioning and the LTA Cys13Arg polymorphism in 351 individuals with schizophrenia, 122 with bipolar disorder, and 160 controls [7].
  • In older women, Minnesota LTA (386 +/- 228 kcal/day) and Caltrac (379 +/- 162 kcal/day) underestimated physical activity by approximately 55% compared with DLW (873 +/- 244 kcal/day) [8].
  • This study applies Latent Transition Analysis (LTA; Collins & Wugalter, 1992; Collins, Wugalter, & Rousculp, 1991) to movement through the stages of change for smoking cessation [9].

High impact information on LTA

  • Disruption of the LT/TNF/LIGHT network alleviates inflammation in certain autoimmune disease models, but decreases resistance to selected pathogens [10].
  • LT is induced in an antigen-specific MHC restricted fashion from class I and class II restricted T cells [11].
  • Viral infection is also associated with LT production by lymphoid cells [11].
  • These findings provide a molecular model of how LTA expression may be genetically regulated by allele-specific recruitment of the transcriptional repressor ABF-1 [12].
  • By detailed haplotypic analysis of the locus, we identified a single-nucleotide polymorphism (SNP) at LTA+80 as a main predictor of LTA protein production by human B cells [12].

Chemical compound and disease context of LTA


Biological context of LTA

  • In vitro functional analyses indicated that one SNP in the coding region of LTA, which changed an amino-acid residue from threonine to asparagine (Thr26Asn), effected a twofold increase in induction of several cell-adhesion molecules, including VCAM1, in vascular smooth-muscle cells of human coronary artery [1].
  • RESULTS: Significant differences in LTA-TNF haplotype frequencies were observed between different subtypes of HLA-DRB1*04 [17].
  • To determine whether polymorphisms in the 5' flanking region of the TNFA gene (-1031C/T, -863C/A, and -857C/T) and an NcoI polymorphism in the TNFB gene (LTA NcoI) are associated with the development of asthma, we performed transmission disequilibrium tests of families identified through children with atopic asthma [18].
  • Here three examples of microsatellites in the human major histocompatibility complex (HLA) are investigated, a (GT)n microsatellite situated 2 kb 5' off the lymphotoxin alpha (LTA) gene, a (GAA)n block in the 5' part of the HLA-F gene and a composite (GT)n(GA)m stretch in the second intron of HLA-DRBl genes [19].
  • Haplotype analysis of a 100 kb region spanning TNF-LTA identifies a polymorphism in the LTA promoter region that is associated with atopic asthma susceptibility in Japan [20].

Anatomical context of LTA

  • Tumour necrosis factors, TNF-alpha and TNF-beta (previously called lymphotoxin), are the products of activated monocytes and lymphocytes, respectively, and both have recently been purified, sequenced and cloned by recombinant DNA methods, revealing 35% identity and 50% homology in the amino-acid sequence [21].
  • Enriched lymphocyte preparations incubated with the staphylococcal toxin produced significant levels of TNF-like activity that is not neutralized by anti-rHuTNF antibodies and is likely to be lymphotoxin (LT or TNF-beta) [22].
  • The highest amounts of TNFBP were seen in the sera of patients with B cell malignancies including hairy cell leukemia (HCL) and type B chronic lymphocytic leukemia [23].
  • Normal B lymphocytes released both IL-1 and TNF/LT activities for four days after activation in vitro; however, production of these cytokines ceased at the final stage of plasma cell [24].
  • These studies suggest that activated T cells through the secretion of LT can in turn activate the local endothelial lining so as to promote homing and extravasation of inflammatory cells [25].

Associations of LTA with chemical compounds

  • The lymphokine tumor necrosis factor (TNF) has a well-defined role as an inducer of inflammatory responses; however, the function of the structurally related molecule lymphotoxin (LT alpha) is unknown [5].
  • Low concentrations of TNF-alpha were produced in response to both IL-12 and IL-7, with little or no TNF-beta production [26].
  • We have investigated the correlation between different tumor necrosis factor (TNF) and class II major histocompatibility complex alleles in the lipopolysaccharide- or phytohemagglutinin-induced secretion of TNF-alpha and TNF-beta by human monocytes and peripheral blood mononuclear cells in 87 unrelated Danish male individuals [27].
  • No association was found with acetylcholine-receptor levels or disease severity for any of the TNFA or TNFB polymorphisms [28].
  • Concentrations of triglyceride rose significantly with increasing tertile only in subjects with a LT-alpha AA genotype [29].
  • Homozygosity for the LTA +80A allele correlated with the lowest levels of plasmatic tumor-necrosis factor-alpha [30].

Physical interactions of LTA


Enzymatic interactions of LTA

  • Examination of enzyme-treated recombinant cytokines by gel electrophoresis revealed that cathepsin-G cleaved LT into a 12.6-kDa fragment and leukocyte elastase fragmented LT into a 14.1-kDa product [35].

Regulatory relationships of LTA

  • IL-1 beta transcripts were expressed in fibroblastic and atypical cultures and TNF beta transcripts were expressed in syncytial and transitional cultures only [36].
  • LT enhances the proliferation of activated B cells and augments B cell proliferation induced by IL-2 [37].
  • These findings demonstrate that cell-surface LT-alpha is expressed in association with LT-beta on activated normal B cells and neoplastic B cells representing an activated state [38].
  • In addition TNF-beta was induced in 3/10 and IFN-gamma in 5/10 non-responders [39].
  • It appears TGF-beta 1 can down-regulate LT mRNA syntheses, mLT expression, and sLT secretion of human T-LAK cells in vitro [40].

Other interactions of LTA


Analytical, diagnostic and therapeutic context of LTA

  • To determine the molecular basis of this disparity between LT and TNF the receptor binding characteristics of rTNF and rLT were investigated by direct and competitive radioligand assays on the II-23.D7 T hybridoma, and for comparison, anti-CD3 activated human T lymphocytes [45].
  • Adding IVIg 24 h after SPE-A stimulation also resulted in reduced blast transformation and decreased synthesis of IFN-gamma and TNF-beta [46].
  • Immunoprecipitation experiments with anti-LT monoclonal antibody (MAb) 9B9 from cell-surface radioiodinated JOK-I cells revealed that a cell-surface lymphotoxin molecule (25 kDa) is expressed in association with a 33-kDa molecule [38].
  • Tumor necrosis factor alpha (TNFa) and lymphotoxin (LT) or TNF beta are closely linked cytokines produced by macrophages and activated T lymphocytes, which play important regulatory roles in the immune response to allografts [47].
  • A polymerase chain reaction sequence-specific primer (PCR-SSP) system was developed to type nine biallelic polymorphisms, three in each of the TNF alpha, LT alpha and IL-10 genes [48].


  1. Functional SNPs in the lymphotoxin-alpha gene that are associated with susceptibility to myocardial infarction. Ozaki, K., Ohnishi, Y., Iida, A., Sekine, A., Yamada, R., Tsunoda, T., Sato, H., Sato, H., Hori, M., Nakamura, Y., Tanaka, T. Nat. Genet. (2002) [Pubmed]
  2. Risk of spontaneous preterm birth is associated with common proinflammatory cytokine polymorphisms. Engel, S.A., Erichsen, H.C., Savitz, D.A., Thorp, J., Chanock, S.J., Olshan, A.F. Epidemiology (Cambridge, Mass.) (2005) [Pubmed]
  3. Polymorphisms in the tumor necrosis factor and lymphotoxin-alpha gene region and preeclampsia. Lachmeijer, A.M., Crusius, J.B., Pals, G., Dekker, G.A., Arngrímsson, R., ten Kate, L.P. Obstetrics and gynecology. (2001) [Pubmed]
  4. Effects of lymphotoxin-alpha gene and galectin-2 gene polymorphisms on inflammatory biomarkers, cellular adhesion molecules and risk of coronary heart disease. Asselbergs, F.W., Pai, J.K., Rexrode, K.M., Hunter, D.J., Rimm, E.B. Clin. Sci. (2007) [Pubmed]
  5. Lymphotoxin beta, a novel member of the TNF family that forms a heteromeric complex with lymphotoxin on the cell surface. Browning, J.L., Ngam-ek, A., Lawton, P., DeMarinis, J., Tizard, R., Chow, E.P., Hession, C., O'Brine-Greco, B., Foley, S.F., Ware, C.F. Cell (1993) [Pubmed]
  6. Cerebral pattern of pro- and anti-inflammatory cytokines in dementias. Tarkowski, E., Liljeroth, A.M., Minthon, L., Tarkowski, A., Wallin, A., Blennow, K. Brain Res. Bull. (2003) [Pubmed]
  7. The lymphotoxin Cys13Arg polymorphism and cognitive functioning in individuals with schizophrenia. Dickerson, F., Boronow, J., Stallings, C., Origoni, A., Yolken, R. Schizophr. Res. (2007) [Pubmed]
  8. Assessment of physical activity in older individuals: a doubly labeled water study. Starling, R.D., Matthews, D.E., Ades, P.A., Poehlman, E.T. J. Appl. Physiol. (1999) [Pubmed]
  9. Latent transition analysis to the stages of change for smoking cessation. Martin, R.A., Velicer, W.F., Fava, J.L. Addictive behaviors. (1996) [Pubmed]
  10. Network communications: lymphotoxins, LIGHT, and TNF. Ware, C.F. Annu. Rev. Immunol. (2005) [Pubmed]
  11. Lymphotoxin. Paul, N.L., Ruddle, N.H. Annu. Rev. Immunol. (1988) [Pubmed]
  12. Allele-specific repression of lymphotoxin-alpha by activated B cell factor-1. Knight, J.C., Keating, B.J., Kwiatkowski, D.P. Nat. Genet. (2004) [Pubmed]
  13. Polymorphisms at position -308 in the promoter region of the TNF-alpha and in the first intron of the TNF-beta genes and spontaneous and lipopolysaccharide-induced TNF-alpha release in sarcoidosis. Somoskövi, A., Zissel, G., Seitzer, U., Gerdes, J., Schlaak, M., Müller-QuernheimJ, n.u.l.l. Cytokine (1999) [Pubmed]
  14. Association of TNF-alpha and TNF-beta gene polymorphism with steroid receptor expression in breast cancer patients. Kamali-Sarvestani, E., Gharesi-Fard, B., Sarvari, J., Talei, A.A. Pathol. Oncol. Res. (2005) [Pubmed]
  15. DNA methylation profiles in the human genes for tumor necrosis factors alpha and beta in subpopulations of leukocytes and in leukemias. Kochanek, S., Radbruch, A., Tesch, H., Renz, D., Doerfler, W. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  16. Cytokine regulation of adenylate cyclase activity in LLC-PK1 cells. Anderson, R.J., Breckon, R. Kidney Int. (1992) [Pubmed]
  17. The effect of HLA-DR on susceptibility to rheumatoid arthritis is influenced by the associated lymphotoxin alpha-tumor necrosis factor haplotype. Newton, J., Brown, M.A., Milicic, A., Ackerman, H., Darke, C., Wilson, J.N., Wordsworth, B.P., Kwiatkowski, D. Arthritis Rheum. (2003) [Pubmed]
  18. Association between TNFA polymorphism and the development of asthma in the Japanese population. Noguchi, E., Yokouchi, Y., Shibasaki, M., Inudou, M., Nakahara, S., Nogami, T., Kamioka, M., Yamakawa-Kobayashi, K., Ichikawa, K., Matsui, A., Arinami, T. Am. J. Respir. Crit. Care Med. (2002) [Pubmed]
  19. On simple repetitive DNA sequences and complex diseases. Epplen, C., Santos, E.J., Mäueler, W., van Helden, P., Epplen, J.T. Electrophoresis (1997) [Pubmed]
  20. Haplotype analysis of a 100 kb region spanning TNF-LTA identifies a polymorphism in the LTA promoter region that is associated with atopic asthma susceptibility in Japan. Migita, O., Noguchi, E., Koga, M., Jian, Z., Shibasaki, M., Migita, T., Ito, S., Ichikawa, K., Matsui, A., Arinami, T. Clin. Exp. Allergy (2005) [Pubmed]
  21. Characterization of receptors for human tumour necrosis factor and their regulation by gamma-interferon. Aggarwal, B.B., Eessalu, T.E., Hass, P.E. Nature (1985) [Pubmed]
  22. Toxic shock syndrome toxin 1 as an inducer of human tumor necrosis factors and gamma interferon. Jupin, C., Anderson, S., Damais, C., Alouf, J.E., Parant, M. J. Exp. Med. (1988) [Pubmed]
  23. High levels of circulating soluble receptors for tumor necrosis factor in hairy cell leukemia and type B chronic lymphocytic leukemia. Digel, W., Porzsolt, F., Schmid, M., Herrmann, F., Lesslauer, W., Brockhaus, M. J. Clin. Invest. (1992) [Pubmed]
  24. Production of interleukin-1 by bone marrow myeloma cells. Cozzolino, F., Torcia, M., Aldinucci, D., Rubartelli, A., Miliani, A., Shaw, A.R., Lansdorp, P.M., Di Guglielmo, R. Blood (1989) [Pubmed]
  25. Activation of cultured human endothelial cells by recombinant lymphotoxin: comparison with tumor necrosis factor and interleukin 1 species. Pober, J.S., Lapierre, L.A., Stolpen, A.H., Brock, T.A., Springer, T.A., Fiers, W., Bevilacqua, M.P., Mendrick, D.L., Gimbrone, M.A. J. Immunol. (1987) [Pubmed]
  26. A comparative study of IL-12 (cytotoxic lymphocyte maturation factor)-, IL-2-, and IL-7-induced effects on immunomagnetically purified CD56+ NK cells. Naume, B., Gately, M., Espevik, T. J. Immunol. (1992) [Pubmed]
  27. Association of tumor necrosis factor (TNF) and class II major histocompatibility complex alleles with the secretion of TNF-alpha and TNF-beta by human mononuclear cells: a possible link to insulin-dependent diabetes mellitus. Pociot, F., Briant, L., Jongeneel, C.V., Mölvig, J., Worsaae, H., Abbal, M., Thomsen, M., Nerup, J., Cambon-Thomsen, A. Eur. J. Immunol. (1993) [Pubmed]
  28. TNFA and TNFB polymorphisms in myasthenia gravis. Skeie, G.O., Pandey, J.P., Aarli, J.A., Gilhus, N.E. Arch. Neurol. (1999) [Pubmed]
  29. Role of single nucleotide polymorphisms of pro-inflammatory cytokine genes in the relationship between serum lipids and inflammatory parameters, and the lipid-lowering effect of fish oil in healthy males. Markovic, O., O'Reilly, G., Fussell, H.M., Turner, S.J., Calder, P.C., Howell, W.M., Grimble, R.F. Clinical nutrition (Edinburgh, Scotland) (2004) [Pubmed]
  30. Polymorphisms in the gene for lymphotoxin-alpha predispose to chronic Chagas cardiomyopathy. Ramasawmy, R., Fae, K.C., Cunha-Neto, E., Müller, N.G., Cavalcanti, V.L., Ferreira, R.C., Drigo, S.A., Ianni, B., Mady, C., Goldberg, A.C., Kalil, J. J. Infect. Dis. (2007) [Pubmed]
  31. Mechanisms of action of the tumor necrosis factor and lymphotoxin ligand-receptor system. Warzocha, K., Bienvenu, J., Coiffier, B., Salles, G. Eur. Cytokine Netw. (1995) [Pubmed]
  32. Role of novel biological therapies in psoriatic arthritis: effects on joints and skin. Braun, J., Sieper, J. BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy. (2003) [Pubmed]
  33. Functional variation in LGALS2 confers risk of myocardial infarction and regulates lymphotoxin-alpha secretion in vitro. Ozaki, K., Inoue, K., Sato, H., Iida, A., Ohnishi, Y., Sekine, A., Sato, H., Odashiro, K., Nobuyoshi, M., Hori, M., Nakamura, Y., Tanaka, T. Nature (2004) [Pubmed]
  34. Activation of the lymphotoxin beta receptor by cross-linking induces chemokine production and growth arrest in A375 melanoma cells. Degli-Esposti, M.A., Davis-Smith, T., Din, W.S., Smolak, P.J., Goodwin, R.G., Smith, C.A. J. Immunol. (1997) [Pubmed]
  35. Cathepsin-G and leukocyte elastase inactivate human tumor necrosis factor and lymphotoxin. Scuderi, P., Nez, P.A., Duerr, M.L., Wong, B.J., Valdez, C.M. Cell. Immunol. (1991) [Pubmed]
  36. RT-PCR detection of cytokine transcripts in a series of cultured human meningiomas. Boyle-Walsh, E., Birch, M., Gallagher, J.A., Speirs, V., White, M.C., Shenkin, A., Fraser, W.D. J. Pathol. (1996) [Pubmed]
  37. Lymphotoxin-alpha is an autocrine growth factor for chronic lymphocytic leukemia B cells. Kulmburg, P., Radke, M., Digel, W. Leukemia (1998) [Pubmed]
  38. Lymphotoxin-alpha/beta heterodimer is expressed on leukemic hairy cells and activated human B lymphocytes. Mapara, M.Y., Bargou, R.C., Beck, C., Heilig, B., Dörken, B., Moldenhauer, G. Int. J. Cancer (1994) [Pubmed]
  39. Immune changes in peripheral blood resulting from locally directed interleukin-2 therapy in squamous cell carcinoma of the head and neck. Dadian, G., Riches, P.G., Henderson, D.C., MacLennan, K., Lorentzos, A., Moore, J., Hobbs, J.R., Gore, M.E. Eur. J. Cancer, B, Oral Oncol. (1993) [Pubmed]
  40. Transforming growth factor-beta 1 down-regulates expression of membrane-associated lymphotoxin and secretion of soluble lymphotoxin by human lymphokine-activated killer T cells in vitro. Abe, Y., Miyake, M., Osuka, Y., Kimura, S., Granger, G.A., Gatanaga, T. Lymphokine Cytokine Res. (1992) [Pubmed]
  41. Characterization of surface lymphotoxin forms. Use of specific monoclonal antibodies and soluble receptors. Browning, J.L., Dougas, I., Ngam-ek, A., Bourdon, P.R., Ehrenfels, B.N., Miatkowski, K., Zafari, M., Yampaglia, A.M., Lawton, P., Meier, W. J. Immunol. (1995) [Pubmed]
  42. In situ expression of cytokines in human heart allografts. Van Hoffen, E., Van Wichen, D., Stuij, I., De Jonge, N., Klöpping, C., Lahpor, J., Van Den Tweel, J., Gmelig-Meyling, F., De Weger, R. Am. J. Pathol. (1996) [Pubmed]
  43. Identification of cysteine-rich domains of the type 1 tumor necrosis factor receptor involved in ligand binding. Marsters, S.A., Frutkin, A.D., Simpson, N.J., Fendly, B.M., Ashkenazi, A. J. Biol. Chem. (1992) [Pubmed]
  44. Stimulation of human T-cell proliferation by specific activation of the 75-kDa tumor necrosis factor receptor. Tartaglia, L.A., Goeddel, D.V., Reynolds, C., Figari, I.S., Weber, R.F., Fendly, B.M., Palladino, M.A. J. Immunol. (1993) [Pubmed]
  45. Characterization of the receptor for tumor necrosis factor (TNF) and lymphotoxin (LT) on human T lymphocytes. TNF and LT differ in their receptor binding properties and the induction of MHC class I proteins on a human CD4+ T cell hybridoma. Andrews, J.S., Berger, A.E., Ware, C.F. J. Immunol. (1990) [Pubmed]
  46. Lymphokine production induced by streptococcal pyrogenic exotoxin-A is selectively down-regulated by pooled human IgG. Skansén-Saphir, U., Andersson, J., Björk, L., Andersson, U. Eur. J. Immunol. (1994) [Pubmed]
  47. Inhibition of the effects of TNF in renal allograft recipients using recombinant human dimeric tumor necrosis factor receptors. Eason, J.D., Wee, S., Kawai, T., Hong, H.Z., Powelson, J.A., Widmer, M.B., Cosimi, A.B. Transplantation (1995) [Pubmed]
  48. Cytokine (TNF alpha, LT alpha and IL-10) polymorphisms in inflammatory bowel diseases and normal controls: differential effects on production and allele frequencies. Koss, K., Satsangi, J., Fanning, G.C., Welsh, K.I., Jewell, D.P. Genes Immun. (2000) [Pubmed]
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