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Gene Review

Lta  -  lymphotoxin A

Mus musculus

Synonyms: LT, LT-[a], LT-alpha, LT[a], LTalpha, ...
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Disease relevance of Lta


High impact information on Lta

  • Studies over the past few years have identified lymphotoxin as a critical signaling molecule not only for the organogenesis of secondary lymphoid tissues but for the maintenance of aspects of their microarchitecture as well [5].
  • However, it differs from TNF and LT in a number of biochemical and functional properties [6].
  • We also evaluated four established cell lines derived from three other patients with myeloma, and found a similar pattern of lymphotoxin expression in each [7].
  • While Py LT mice exhibit no phenotype, Py MT mice develop multifocal tumors of the vascular endothelium [8].
  • Recently, a number of bone-resorbing leukocyte cytokines have been identified, including interleukin-1, lymphotoxin, and tumor necrosis factor [7].

Chemical compound and disease context of Lta


Biological context of Lta

  • PP formation of both Il7ra-/- and Lta-/- mice is impaired from step I, suggesting involvement of the two molecules at the same timing in PP organogenesis [14].
  • Spleen morphology and antibody response were investigated in wild-type, TNFR1-/-, TNFR2-/- and TNF/LT alpha-/- mice immunized with SRBC [15].
  • Anti-LT-beta-R mAbs were also identified that inhibited ligand-induced cell death, whereas others were found to potentiate the activity of the ligand when added in solution [16].
  • Exposure to LT beta-R-Ig during gestation disrupted lymph node development and splenic architecture in the progeny indicating that both effects are mediated by the surface LT alpha/beta complex [17].
  • The yield of CD11c(+) major histocompatibility complex (MHC) class II(+) DCs generated from TNF/LTalpha/LTbeta(-/-) BM culture was significantly reduced compared with wt BM culture [18].

Anatomical context of Lta


Associations of Lta with chemical compounds


Physical interactions of Lta

  • LT-/- chimeras, which lack both secreted LTalpha3 and membrane-bound LTbeta (LT1beta2 and LT2beta1), were highly susceptible and succumbed 5 wk after infection [3].
  • By analysis of the DNA sequences around 180-300 bases upstream of the transcription initiation point of the mouse TNF-beta gene, we demonstrate that there is a STAT5 binding site which is essential to the inducibility of the TNF-beta gene [26].
  • Because type 1 TNF receptor binds both TNF and lymphotoxin-a, we used TNF-deficient mice to determine the specific role of TNF in the host resistance to BCG infection [27].
  • Furthermore, using kinase inhibitors, we revealed that p38 MAP kinase is involved in the formation of -130EBS-protein complex and the subsequent transcriptional activation of TNF-beta gene in response to IL-2 stimulation [28].
  • Exposure of these cells to Bay 11-7082 (an inhibitor of IkappaB phosphorylation and, therefore, NF-kappaB activation) abrogated NF-kappaB binding and lymphotoxin production in a dose-dependent manner in both Z-43 and 3A4 cells [29].

Regulatory relationships of Lta

  • Inhibition of LT alpha/beta signaling using LT betaR-Ig or a blocking monoclonal antibody against murine LT beta had profound effects [30].
  • Inflammatory foci consistently correlated with lymphotoxin up-regulation and ectopic induction of FDC-M1+ cells expressing the normal cellular prion protein PrPC [31].
  • In germinal centres the feedback loop is overridden, with B-cell lymphotoxin alpha1beta2 expression being induced by a mechanism independent of BLC [32].
  • The data in this study demonstrate that FDC organization and GC formation are controlled by both LT-alpha-expressing BM-derived cells and by TNFR-I-expressing non-BM-derived cells [33].
  • METHODS: Soluble LTbeta receptor (LTbetaR) immunoglobulin fusion protein was used to inhibit the LTalpha/beta/light axis in two independent rodent models of colitis: CD45RBhi CD4(+)-reconstituted SCID mice and bone marrow-transplanted tg26 mice (BM --> tg26) [34].

Other interactions of Lta

  • Here we show that LTalpha, not TNFalpha, is the principal mediator of murine CM [4].
  • TNF/LT alpha-/- mice, which have a complete disruption of the TNF/LT alpha signaling system including the LT beta-receptor pathway, displayed an abnormal microarchitecture, and isotype switch did not take place [15].
  • In summary, the p55 receptor for TNF selectively mediates organogenesis of Peyer's patches throughout ontogeny, suggesting that the effects of LT-alpha on the development of lymphoid organs may be mediated by distinct receptors, each functioning in an organ-specific context [21].
  • Effector cell-derived lymphotoxin alpha and Fas ligand, but not perforin, promote Tc1 and Tc2 effector cell-mediated tumor therapy in established pulmonary metastases [35].
  • Furthermore, when lethally irradiated recombination activating gene (RAG)-1-deficient (RAG-1(-/-)) mice that had received spleen cells from LT-alpha-/- mice were immunized with sheep red blood cells, they failed to generate PNA+ clusters in the reconstituted spleen but showed robust PNA+ clusters in the reconstituted LNs [36].

Analytical, diagnostic and therapeutic context of Lta

  • When recombinant mLT alpha was produced by either of several methods, the protein had a very low specific activity relative to that of human LT alpha in the conventional WEHI 164 cytotoxicity bioassay [37].
  • LT-alpha detected by immunoassay in serum was not bioactive, in contrast to that produced in cell culture [38].
  • Comparative sequence analysis of TNF and LT localized the trypanocidal region, and synthetic peptides were trypanolytic [39].
  • This approach overcame the problems related to the lack of lymph nodes that results from LTalpha gene targeting [40].
  • The results show a positive correlation between the presence of TNF and/or LT mRNA and the 51Cr-releasing activity present in the cell culture medium [41].


  1. Signaling via LTbetaR on the lamina propria stromal cells of the gut is required for IgA production. Kang, H.S., Chin, R.K., Wang, Y., Yu, P., Wang, J., Newell, K.A., Fu, Y.X. Nat. Immunol. (2002) [Pubmed]
  2. Tumor necrosis factor alpha and lymphotoxin alpha are not required for induction of acute experimental autoimmune encephalomyelitis. Frei, K., Eugster, H.P., Bopst, M., Constantinescu, C.S., Lavi, E., Fontana, A. J. Exp. Med. (1997) [Pubmed]
  3. Secreted lymphotoxin-alpha is essential for the control of an intracellular bacterial infection. Roach, D.R., Briscoe, H., Saunders, B., France, M.P., Riminton, S., Britton, W.J. J. Exp. Med. (2001) [Pubmed]
  4. Locally up-regulated lymphotoxin alpha, not systemic tumor necrosis factor alpha, is the principle mediator of murine cerebral malaria. Engwerda, C.R., Mynott, T.L., Sawhney, S., De Souza, J.B., Bickle, Q.D., Kaye, P.M. J. Exp. Med. (2002) [Pubmed]
  5. Development and maturation of secondary lymphoid tissues. Fu, Y.X., Chaplin, D.D. Annu. Rev. Immunol. (1999) [Pubmed]
  6. Identification, isolation, and characterization of a novel cytotoxin in murine cytolytic lymphocytes. Liu, C.C., Steffen, M., King, F., Young, J.D. Cell (1987) [Pubmed]
  7. Production of lymphotoxin, a bone-resorbing cytokine, by cultured human myeloma cells. Garrett, I.R., Durie, B.G., Nedwin, G.E., Gillespie, A., Bringman, T., Sabatini, M., Bertolini, D.R., Mundy, G.R. N. Engl. J. Med. (1987) [Pubmed]
  8. Endothelial cell tumors develop in transgenic mice carrying polyoma virus middle T oncogene. Bautch, V.L., Toda, S., Hassell, J.A., Hanahan, D. Cell (1987) [Pubmed]
  9. Membrane lymphotoxin is required for resistance to Theiler's virus infection. Lin, X., Ma, X., Rodriguez, M., Feng, X., Zoecklein, L., Fu, Y.X., Roos, R.P. Int. Immunol. (2003) [Pubmed]
  10. Lymphotoxin-alpha deficiency completely protects C57BL/6 mice from developing clinical experimental autoimmune myasthenia gravis. Goluszko, E., Hjelmström, P., Deng, C., Poussin, M.A., Ruddle, N.H., Christadoss, P. J. Neuroimmunol. (2001) [Pubmed]
  11. The role of lipopolysaccharide, pro-inflammatory cytokines and bacterial superantigens in the transcriptional regulation of lymphotoxin alpha and beta in mouse splenocytes. Zinetti, M., Agyekum, S., Evans, T., Polak, J., Cohen, J. Cytokine (1998) [Pubmed]
  12. Novel lymphotoxin alpha (LTalpha) knockout mice with unperturbed tumor necrosis factor expression: reassessing LTalpha biological functions. Liepinsh, D.J., Grivennikov, S.I., Klarmann, K.D., Lagarkova, M.A., Drutskaya, M.S., Lockett, S.J., Tessarollo, L., McAuliffe, M., Keller, J.R., Kuprash, D.V., Nedospasov, S.A. Mol. Cell. Biol. (2006) [Pubmed]
  13. Contribution of the lymphotoxin beta receptor to liver regeneration. Anders, R.A., Subudhi, S.K., Wang, J., Pfeffer, K., Fu, Y.X. J. Immunol. (2005) [Pubmed]
  14. IL-7 receptor alpha+ CD3(-) cells in the embryonic intestine induces the organizing center of Peyer's patches. Yoshida, H., Honda, K., Shinkura, R., Adachi, S., Nishikawa, S., Maki, K., Ikuta, K., Nishikawa, S.I. Int. Immunol. (1999) [Pubmed]
  15. Differentiation of follicular dendritic cells and full antibody responses require tumor necrosis factor receptor-1 signaling. Le Hir, M., Bluethmann, H., Kosco-Vilbois, M.H., Müller, M., di Padova, F., Moore, M., Ryffel, B., Eugster, H.P. J. Exp. Med. (1996) [Pubmed]
  16. Signaling through the lymphotoxin beta receptor induces the death of some adenocarcinoma tumor lines. Browning, J.L., Miatkowski, K., Sizing, I., Griffiths, D., Zafari, M., Benjamin, C.D., Meier, W., Mackay, F. J. Exp. Med. (1996) [Pubmed]
  17. Surface lymphotoxin alpha/beta complex is required for the development of peripheral lymphoid organs. Rennert, P.D., Browning, J.L., Mebius, R., Mackay, F., Hochman, P.S. J. Exp. Med. (1996) [Pubmed]
  18. Distinct contributions of TNF and LT cytokines to the development of dendritic cells in vitro and their recruitment in vivo. Abe, K., Yarovinsky, F.O., Murakami, T., Shakhov, A.N., Tumanov, A.V., Ito, D., Drutskaya, L.N., Pfeffer, K., Kuprash, D.V., Komschlies, K.L., Nedospasov, S.A. Blood (2003) [Pubmed]
  19. Distinct roles in lymphoid organogenesis for lymphotoxins alpha and beta revealed in lymphotoxin beta-deficient mice. Koni, P.A., Sacca, R., Lawton, P., Browning, J.L., Ruddle, N.H., Flavell, R.A. Immunity (1997) [Pubmed]
  20. Lymphotoxin alpha/beta and tumor necrosis factor are required for stromal cell expression of homing chemokines in B and T cell areas of the spleen. Ngo, V.N., Korner, H., Gunn, M.D., Schmidt, K.N., Riminton, D.S., Cooper, M.D., Browning, J.L., Sedgwick, J.D., Cyster, J.G. J. Exp. Med. (1999) [Pubmed]
  21. Defective Peyer's patch organogenesis in mice lacking the 55-kD receptor for tumor necrosis factor. Neumann, B., Luz, A., Pfeffer, K., Holzmann, B. J. Exp. Med. (1996) [Pubmed]
  22. Targeted disruption of LIGHT causes defects in costimulatory T cell activation and reveals cooperation with lymphotoxin beta in mesenteric lymph node genesis. Scheu, S., Alferink, J., Pötzel, T., Barchet, W., Kalinke, U., Pfeffer, K. J. Exp. Med. (2002) [Pubmed]
  23. 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]
  24. Molecular regulation of tumor necrosis factor-alpha and lymphotoxin production in T cells. Inhibition by prostaglandin E2. Ferreri, N.R., Sarr, T., Askenase, P.W., Ruddle, N.H. J. Biol. Chem. (1992) [Pubmed]
  25. Differential regulation of lymphotoxin (LT), lymphotoxin-beta (LT-beta), and TNF-alpha in murine T cell clones activated through the TCR. Millet, I., Ruddle, N.H. J. Immunol. (1994) [Pubmed]
  26. Jak-STAT pathway is involved in the induction of TNF-beta gene during stimulation by IL-2. Lu, L., Zhu, J., Zheng, Z., Yan, M., Xu, W., Sun, L., Theze, J., Liu, X. Eur. J. Immunol. (1998) [Pubmed]
  27. Correction of defective host response to Mycobacterium bovis BCG infection in TNF-deficient mice by bone marrow transplantation. Jacobs, M., Marino, M.W., Brown, N., Abel, B., Bekker, L.G., Quesniaux, V.J., Fick, L., Ryffel, B. Lab. Invest. (2000) [Pubmed]
  28. The p38 MAPK pathway is involved in the IL-2 induction of TNF-beta gene via the EBS element. Xu, W., Yan, M., Lu, L., Sun, L., Theze, J., Zheng, Z., Liu, X. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  29. Autocrine lymphotoxin production in Epstein-Barr virus-immortalized B cells: induction via NF-kappaB activation mediated by EBV-derived latent membrane protein 1. Thompson, M.P., Aggarwal, B.B., Shishodia, S., Estrov, Z., Kurzrock, R. Leukemia (2003) [Pubmed]
  30. Lymphotoxin but not tumor necrosis factor functions to maintain splenic architecture and humoral responsiveness in adult mice. Mackay, F., Majeau, G.R., Lawton, P., Hochman, P.S., Browning, J.L. Eur. J. Immunol. (1997) [Pubmed]
  31. Chronic lymphocytic inflammation specifies the organ tropism of prions. Heikenwalder, M., Zeller, N., Seeger, H., Prinz, M., Klöhn, P.C., Schwarz, P., Ruddle, N.H., Weissmann, C., Aguzzi, A. Science (2005) [Pubmed]
  32. A chemokine-driven positive feedback loop organizes lymphoid follicles. Ansel, K.M., Ngo, V.N., Hyman, P.L., Luther, S.A., Förster, R., Sedgwick, J.D., Browning, J.L., Lipp, M., Cyster, J.G. Nature (2000) [Pubmed]
  33. Distinct roles of lymphotoxin alpha and the type I tumor necrosis factor (TNF) receptor in the establishment of follicular dendritic cells from non-bone marrow-derived cells. Matsumoto, M., Fu, Y.X., Molina, H., Huang, G., Kim, J., Thomas, D.A., Nahm, M.H., Chaplin, D.D. J. Exp. Med. (1997) [Pubmed]
  34. Both the lymphotoxin and tumor necrosis factor pathways are involved in experimental murine models of colitis. Mackay, F., Browning, J.L., Lawton, P., Shah, S.A., Comiskey, M., Bhan, A.K., Mizoguchi, E., Terhorst, C., Simpson, S.J. Gastroenterology (1998) [Pubmed]
  35. Effector cell-derived lymphotoxin alpha and Fas ligand, but not perforin, promote Tc1 and Tc2 effector cell-mediated tumor therapy in established pulmonary metastases. Dobrzanski, M.J., Reome, J.B., Hollenbaugh, J.A., Hylind, J.C., Dutton, R.W. Cancer Res. (2004) [Pubmed]
  36. Independent signals regulate development of primary and secondary follicle structure in spleen and mesenteric lymph node. Fu, Y.X., Huang, G., Matsumoto, M., Molina, H., Chaplin, D.D. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  37. Cytotoxic activities of recombinant soluble murine lymphotoxin-alpha and lymphotoxin-alpha beta complexes. Mackay, F., Bourdon, P.R., Griffiths, D.A., Lawton, P., Zafari, M., Sizing, I.D., Miatkowski, K., Ngam-ek, A., Benjamin, C.D., Hession, C., Ambrose, C.M., Meier, W., Browning, J.L. J. Immunol. (1997) [Pubmed]
  38. Lymphotoxin-alpha (TNF-beta) during sepsis. Sriskandan, S., Moyes, D., Lemm, G., Cohen, J. Cytokine (1996) [Pubmed]
  39. Mapping the lectin-like activity of tumor necrosis factor. Lucas, R., Magez, S., De Leys, R., Fransen, L., Scheerlinck, J.P., Rampelberg, M., Sablon, E., De Baetselier, P. Science (1994) [Pubmed]
  40. Challenging cytokine redundancy: inflammatory cell movement and clinical course of experimental autoimmune encephalomyelitis are normal in lymphotoxin-deficient, but not tumor necrosis factor-deficient, mice. Sean Riminton, D., Körner, H., Strickland, D.H., Lemckert, F.A., Pollard, J.D., Sedgwick, J.D. J. Exp. Med. (1998) [Pubmed]
  41. Production of tumor necrosis factor (TNF-alpha) and lymphotoxin (TNF-beta) by murine pre-B and B cell lymphomas. Laskov, R., Lancz, G., Ruddle, N.H., McGrath, K.M., Specter, S., Klein, T., Djeu, J.Y., Friedman, H. J. Immunol. (1990) [Pubmed]
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