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Gene Review

LTB  -  lymphotoxin beta (TNF superfamily, member 3)

Homo sapiens

Synonyms: LT-beta, Lymphotoxin-beta, TNF-C, TNFC, TNFSF3, ...
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Disease relevance of LTB


High impact information on LTB

  • These observations raise the possibility that a surface LT alpha-LT beta complex may have a specific role in immune regulation distinct from the functions ascribed to TNF [1].
  • A receptor specific for human LT-beta was identified, which suggests that cell surface LT may have functions that are distinct from those of secreted LT-alpha [5].
  • Using dominant-negative proteins that inhibit NFAT5 dimerization, we show that NFAT5 regulates expression of the TNFalpha and lymphotoxin-beta genes in osmotically stressed T cells [6].
  • LIGHT is a 29 kDa type II transmembrane protein produced by activated T cells that also engages the receptor for the LTalphabeta heterotrimer but does not form complexes with either LTalpha or LTbeta [7].
  • In contrast, as shown previously and confirmed in this study, LTbeta-deficient mice show much more conserved T/B cell areas and a reduced but preserved capacity to form germinal centers and FDC networks [8].

Chemical compound and disease context of LTB

  • Particular alleles of the tumor necrosis factor gene cluster (TNFA, LTA, LTB) are known to be associated with peculiar clinical forms of sarcoidosis [9].
  • The closely related B-subunits of cholera toxin (CTB) and Escherichia coli heat-labile enterotoxin (LTB) both bind strongly to GM1 ganglioside receptors but LTB can also bind to additional glycolipids and glycoproteins [10].
  • We now report the structure determination and 2.3-A refinement of the CTB mutant Gly 33-->Arg complexed with the GM1 oligosaccharide, as well as the 2.2-A refinement of a Gly 33-->Asp mutant of the closely related Escherichia coli heat-labile enterotoxin B-pentamer (LTB) [11].

Biological context of LTB

  • In investigating the reported upregulation of LT-beta during inflammation, we tested the effects of various proinflammatory and anti-inflammatory cytokines on LT-beta expression [12].
  • In addition, the observation of striking similarities between the mRNA accumulation kinetics of LT-alpha and LT-beta during these treatments indicates tight coupling of expression under certain conditions [12].
  • Membrane-anchored LTbeta expressed on the cell surface in absence of the LTalpha subunit binds the LTbetaR but is functionally inactive in the cell death assay [13].
  • The pattern of LTbeta gene expression was different from that of the other molecules, indicating the existence of distinct mechanisms of gene regulation [14].
  • Skipping out of exon 2 causes a reading frame shift and a premature stop codon in the LTbeta mRNA variant [4].

Anatomical context of LTB


Associations of LTB with chemical compounds


Physical interactions of LTB

  • LT beta is a transmembrane protein that provides the membrane anchor for the attachment to the cell surface of the heteromeric complex of LT alpha and LT beta [23].

Regulatory relationships of LTB


Other interactions of LTB

  • Our data demonstrate an upregulation of LT-beta mRNA by the inflammatory cytokines TNF and LT-alpha [12].
  • These results indicate that the TNF receptor-binding regions of the LTalpha subunit are not necessary for engagement of the LTbetaR, but the LTalpha subunit is required for the assembly of LTbeta into a functional heteromeric ligand [13].
  • RESULTS: The expression of LT-beta in hepatic oval cell and hepatocellular carcinoma cell lines was further investigated, along with its responsiveness to IL-6 and IL-1beta [27].
  • These results implicate TRAF3 as a critical component of the LTbeta R death signaling complex and indicate that at least two independent signaling pathways are initiated by LTbeta R ligation [25].
  • Proliferating human medullary thymocytes can exhibit characteristic T helper cell type 1 cytokine responses exemplified by the immediate early expression of interleukin-2, interferon-gamma, tumor necrosis factor-alpha, and lymphotoxin-beta [28].

Analytical, diagnostic and therapeutic context of LTB


  1. 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]
  2. Differential cytokine expression in EBV positive peripheral T cell lymphomas. Ho, J.W., Liang, R.H., Srivastava, G. MP, Mol. Pathol. (1999) [Pubmed]
  3. Molecular organization of heat-labile enterotoxin genes originating in Escherichia coli of human origin and construction of heat-labile toxoid-producing strains. Yamamoto, T., Yokota, T., Kaji, A. J. Bacteriol. (1981) [Pubmed]
  4. Identification of two lymphotoxin beta isoforms expressed in human lymphoid cell lines and non-Hodgkin's lymphomas. Warzocha, K., Renard, N., Charlot, C., Bienvenu, J., Coiffier, B., Salles, G. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
  5. A lymphotoxin-beta-specific receptor. Crowe, P.D., VanArsdale, T.L., Walter, B.N., Ware, C.F., Hession, C., Ehrenfels, B., Browning, J.L., Din, W.S., Goodwin, R.G., Smith, C.A. Science (1994) [Pubmed]
  6. Bridging the NFAT and NF-kappaB families: NFAT5 dimerization regulates cytokine gene transcription in response to osmotic stress. López-Rodríguez, C., Aramburu, J., Jin, L., Rakeman, A.S., Michino, M., Rao, A. Immunity (2001) [Pubmed]
  7. LIGHT, a new member of the TNF superfamily, and lymphotoxin alpha are ligands for herpesvirus entry mediator. Mauri, D.N., Ebner, R., Montgomery, R.I., Kochel, K.D., Cheung, T.C., Yu, G.L., Ruben, S., Murphy, M., Eisenberg, R.J., Cohen, G.H., Spear, P.G., Ware, C.F. Immunity (1998) [Pubmed]
  8. Complementation of lymphotoxin alpha knockout mice with tumor necrosis factor-expressing transgenes rectifies defective splenic structure and function. Alexopoulou, L., Pasparakis, M., Kollias, G. J. Exp. Med. (1998) [Pubmed]
  9. HLA and sarcoidosis: new pathogenetic insights. Martinetti, M., Luisetti, M., Cuccia, M. Sarcoidosis, vasculitis, and diffuse lung diseases : official journal of WASOG / World Association of Sarcoidosis and Other Granulomatous Disorders. (2002) [Pubmed]
  10. Structural basis for differential receptor binding of cholera and Escherichia coli heat-labile toxins: influence of heterologous amino acid substitutions in the cholera B-subunit. Bäckström, M., Shahabi, V., Johansson, S., Teneberg, S., Kjellberg, A., Miller-Podraza, H., Holmgren, J., Lebens, M. Mol. Microbiol. (1997) [Pubmed]
  11. Structural studies of receptor binding by cholera toxin mutants. Merritt, E.A., Sarfaty, S., Jobling, M.G., Chang, T., Holmes, R.K., Hirst, T.R., Hol, W.G. Protein Sci. (1997) [Pubmed]
  12. Regulation of lymphotoxin-beta by tumor necrosis factor, phorbol myristate acetate, and ionomycin in Jurkat T cells. Voon, D.C., Subrata, L.S., Abraham, L.J. J. Interferon Cytokine Res. (2001) [Pubmed]
  13. The lymphotoxin-alpha (LTalpha) subunit is essential for the assembly, but not for the receptor specificity, of the membrane-anchored LTalpha1beta2 heterotrimeric ligand. Williams-Abbott, L., Walter, B.N., Cheung, T.C., Goh, C.R., Porter, A.G., Ware, C.F. J. Biol. Chem. (1997) [Pubmed]
  14. Expression of genes coding for the tumor necrosis factor and lymphotoxin ligand-receptor system in non-Hodgkin's lymphomas. Warzocha, K., Ribeiro, P., Renard, N., Bienvenu, J., Charlot, C., Coiffier, B., Salles, G. Cancer Immunol. Immunother. (2000) [Pubmed]
  15. 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]
  16. Multiple sclerosis: expression of molecules of the tumor necrosis factor ligand and receptor families in relationship to the demyelinated plaque. Raine, C.S., Bonetti, B., Cannella, B. Rev. Neurol. (Paris) (1998) [Pubmed]
  17. 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]
  18. Tumor necrosis factor-beta in human pregnancy and labor. Laham, N., Van Dunné, F., Abraham, L.J., Farrugia, W., Bendtzen, K., Brennecke, S.P., Rice, G.E. J. Reprod. Immunol. (1997) [Pubmed]
  19. Lymphotoxin and an associated 33-kDa glycoprotein are expressed on the surface of an activated human T cell hybridoma. Browning, J.L., Androlewicz, M.J., Ware, C.F. J. Immunol. (1991) [Pubmed]
  20. Tumor necrosis factor alpha is an autocrine growth factor for normal human B cells. Boussiotis, V.A., Nadler, L.M., Strominger, J.L., Goldfeld, A.E. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  21. Lymphotoxin is expressed as a heteromeric complex with a distinct 33-kDa glycoprotein on the surface of an activated human T cell hybridoma. Androlewicz, M.J., Browning, J.L., Ware, C.F. J. Biol. Chem. (1992) [Pubmed]
  22. Cyclosporin A blocks the expression of lymphotoxin alpha, but not lymphotoxin beta, in human peripheral blood mononuclear cells. Kuprash, D.V., Boitchenko, V.E., Yarovinsky, F.O., Rice, N.R., Nordheim, A., Rühlmann, A., Nedospasov, S.A. Blood (2002) [Pubmed]
  23. 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]
  24. TNF and phorbol esters induce lymphotoxin-beta expression through distinct pathways involving Ets and NF-kappa B family members. Voon, D.C., Subrata, L.S., Karimi, M., Ulgiati, D., Abraham, L.J. J. Immunol. (2004) [Pubmed]
  25. Lymphotoxin-beta receptor signaling complex: role of tumor necrosis factor receptor-associated factor 3 recruitment in cell death and activation of nuclear factor kappaB. VanArsdale, T.L., VanArsdale, S.L., Force, W.R., Walter, B.N., Mosialos, G., Kieff, E., Reed, J.C., Ware, C.F. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  26. Novel markers of the human follicle-associated epithelium identified by genomic profiling and microdissection. Anderle, P., Rumbo, M., Sierro, F., Mansourian, R., Michetti, P., Roberts, M.A., Kraehenbuhl, J.P. Gastroenterology (2005) [Pubmed]
  27. Hepatic expression of the tumor necrosis factor family member lymphotoxin-beta is regulated by interleukin (IL)-6 and IL-1beta: transcriptional control mechanisms in oval cells and hepatoma cell lines. Subrata, L.S., Lowes, K.N., Olynyk, J.K., Yeoh, G.C., Quail, E.A., Abraham, L.J. Liver Int. (2005) [Pubmed]
  28. Role of transcriptional repressor ICER in cyclic AMP-mediated attenuation of cytokine gene expression in human thymocytes. Bodor, J., Habener, J.F. J. Biol. Chem. (1998) [Pubmed]
  29. Signaling through the lymphotoxin-beta receptor stimulates HIV-1 replication alone and in cooperation with soluble or membrane-bound TNF-alpha. Marshall, W.L., Brinkman, B.M., Ambrose, C.M., Pesavento, P.A., Uglialoro, A.M., Teng, E., Finberg, R.W., Browning, J.L., Goldfeld, A.E. J. Immunol. (1999) [Pubmed]
  30. Cloning and expression analysis of the murine lymphotoxin beta gene. Pokholok, D.K., Maroulakou, I.G., Kuprash, D.V., Alimzhanov, M.B., Kozlov, S.V., Novobrantseva, T.I., Turetskaya, R.L., Green, J.E., Nedospasov, S.A. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  31. Expression of lymphotoxin-beta (LT-beta) in chronic inflammatory conditions. Agyekum, S., Church, A., Sohail, M., Krausz, T., Van Noorden, S., Polak, J., Cohen, J. J. Pathol. (2003) [Pubmed]
  32. Lymphotoxin-alpha- and lymphotoxin-beta-deficient mice differ in susceptibility to scrapie: evidence against dendritic cell involvement in neuroinvasion. Oldstone, M.B., Race, R., Thomas, D., Lewicki, H., Homann, D., Smelt, S., Holz, A., Koni, P., Lo, D., Chesebro, B., Flavell, R. J. Virol. (2002) [Pubmed]
  33. cDNA sequence of the lymphotoxin beta chain from a marsupial, Macropus eugenii (Tammar wallaby). Harrison, G.A., Deane, E.M. J. Interferon Cytokine Res. (1999) [Pubmed]
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