Lymphotoxin’s Link to Carcinogenesis: Friend or Foe? From Lymphoid Neogenesis to Hepatocellular Carcinoma and Prostate Cancer

  • Monika Julia Wolf
  • Gitta Maria Seleznik
  • Mathias Heikenwalder
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 691)


Tumor necrosis factor alpha (TNFα) was initially discovered due to its tumor necrotizing activity in mice, leading to the death of vascular endothelial cells. Today, pro- and anti-tumorigenic effects of TNF are discussed and TNF as well as other members of the TNF superfamily (TNFSF) were described to play an important role in the development and maintenance of lymphoid tissue and inflammatory reactions. Notably, recent reports indicate a pivotal role of lymphotoxin (LT), a closely related cytokine, in controlling the development of liver and prostate cancer or nasopharyngeal carcinoma – however by distinct mechanisms. Here, we review the pleiotropic functions attributed to LT, the effects of its deregulation and discuss recent literature on LT’s link to cancer.


Experimental Autoimmune Encephalomyelitis Herpes Virus Entry Mediator Nasopharyngeal Epithelial Cell Lymphoid Tissue Inducer Cell Lymphoid Neogenesis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



We thank Dr. Johannes Haybaeck and Barbara Stecher as well as Jay Tracy for critically reading this chapter. MH is supported by grants of the Oncosuisse Foundation OCS 02113-08-2007, the Novartis Stiftung für Biologisch-Medizinische Forschung (no. 09C62), the “Stiftung zur Schweizerischen Krebsbekämpfung,” the research foundation at the Medical Faculty Zurich, and the “Kurt und Senta Hermann Stiftung.” MJW was supported by a grant of the Roche Research Foundation. MH is a fellow of the Prof. Dr. Max Cloëtta Foundation.


  1. 1.
    Aggarwal BB, Henzel WJ, Moffat B, Kohr WJ, Harkins RN (1985) Primary structure of human lymphotoxin derived from 1788 lymphoblastoid cell line. J Biol Chem 260:2334–2344PubMedGoogle Scholar
  2. 2.
    Aggarwal BB, Moffat B, Harkins RN (1984) Human lymphotoxin. Production by a lymphoblastoid cell line, purification, initial characterization. J Biol Chem 259:686–691PubMedGoogle Scholar
  3. 3.
    An MM, Fan KX, Cao YB, Shen H, Zhang JD, Lu L, Gao PH, Jiang YY (2006) Lymphotoxin beta receptor-Ig protects from T-cell-mediated liver injury in mice through blocking LIGHT/HVEM signaling. Biol Pharm Bull 29:2025–2030CrossRefPubMedGoogle Scholar
  4. 4.
    Anand S, Wang P, Yoshimura K, Choi IH, Hilliard A, Chen YH, Wang CR, Schulick R, Flies AS, Flies DB et al (2006) Essential role of TNF family molecule LIGHT as a cytokine in the pathogenesis of hepatitis. J Clin Invest 116:1045–1051CrossRefPubMedGoogle Scholar
  5. 5.
    Ansel KM, Ngo VN, Hyman PL, Luther SA, Forster R, Sedgwick JD, Browning JL, Lipp M, Cyster JG (2000) A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature 406:309–314CrossRefPubMedGoogle Scholar
  6. 6.
    Baffet G, Braciak TA, Fletcher RG, Gauldie J, Fey GH, Northemann W (1991) Autocrine activity of interleukin 6 secreted by hepatocarcinoma cell lines. Mol Biol Med 8:141–156PubMedGoogle Scholar
  7. 7.
    Balkwill F, Mantovani A (2001) Inflammation and cancer: back to Virchow? Lancet 357:539–545CrossRefPubMedGoogle Scholar
  8. 8.
    Banks TA, Rouse BT, Kerley MK, Blair PJ, Godfrey VL, Kuklin NA, Bouley DM, Thomas J, Kanangat S, Mucenski ML (1995) Lymphotoxin-alpha-deficient mice. Effects on secondary lymphoid organ development and humoral immune responsiveness. J Immunol 155:1685–1693PubMedGoogle Scholar
  9. 9.
    Bossen C, Cachero TG, Tardivel A, Ingold K, Willen L, Dobles M, Scott ML, Maquelin A, Belnoue E, Siegrist CA et al (2008) TACI, unlike BAFF-R, is solely activated by oligomeric BAFF and APRIL to support survival of activated B cells and plasmablasts. Blood 111:1004–1012CrossRefPubMedGoogle Scholar
  10. 10.
    Browning JL (2008) Inhibition of the lymphotoxin pathway as a therapy for autoimmune disease. Immunol Rev 223:202–220CrossRefPubMedGoogle Scholar
  11. 11.
    Browning JL, Allaire N, Ngam-Ek A, Notidis E, Hunt J, Perrin S, Fava RA (2005) Lymphotoxin-beta receptor signaling is required for the homeostatic control of HEV differentiation and function. Immunity 23:539–550CrossRefPubMedGoogle Scholar
  12. 12.
    Browning JL, French LE (2002) Visualization of lymphotoxin-beta and lymphotoxin-beta receptor expression in mouse embryos. J Immunol 168:5079–5087PubMedGoogle Scholar
  13. 13.
    Chen CM, You LR, Hwang LH, Lee YH (1997) Direct interaction of hepatitis C virus core protein with the cellular lymphotoxin-beta receptor modulates the signal pathway of the lymphotoxin-beta receptor. J Virol 71:9417–9426PubMedGoogle Scholar
  14. 14.
    Chen SC, Vassileva G, Kinsley D, Holzmann S, Manfra D, Wiekowski MT, Romani N, Lira SA (2002) Ectopic expression of the murine chemokines CCL21a and CCL21b induces the formation of lymph node-like structures in pancreas, but not skin, of transgenic mice. J Immunol 168:1001–1008PubMedGoogle Scholar
  15. 15.
    Chiang EY, Kolumam GA, Yu X, Francesco M, Ivelja S, Peng I, Gribling P, Shu J, Lee WP, Refino CJ et al (2009) Targeted depletion of lymphotoxin-alpha-expressing TH1 and TH17 cells inhibits autoimmune disease. Nat Med 15:766–773CrossRefPubMedGoogle Scholar
  16. 16.
    Chin RK, Lo JC, Kim O, Blink SE, Christiansen PA, Peterson P, Wang Y, Ware C, Fu YX (2003) Lymphotoxin pathway directs thymic Aire expression. Nat Immunol 4:1121–1127CrossRefPubMedGoogle Scholar
  17. 17.
    Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A (2009) Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis 30:1073–1081CrossRefPubMedGoogle Scholar
  18. 18.
    Compagno M, Lim WK, Grunn A, Nandula SV, Brahmachary M, Shen Q, Bertoni F, Ponzoni M, Scandurra M, Califano A et al (2009) Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma. Nature 459:717–721CrossRefPubMedGoogle Scholar
  19. 19.
    Coussens LM, Shapiro SD, Soloway PD, Werb Z (2001) Models for gain-of-function and loss-of-function of MMPs. Transgenic and gene targeted mice. Methods Mol Biol 151:149–179PubMedGoogle Scholar
  20. 20.
    Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867CrossRefPubMedGoogle Scholar
  21. 21.
    Cuff CA, Sacca R, Ruddle NH (1999) Differential induction of adhesion molecule and chemokine expression by LTalpha3 and LTalphabeta in inflammation elucidates potential mechanisms of mesenteric and peripheral lymph node development. J Immunol 162:5965–5972PubMedGoogle Scholar
  22. 22.
    Cuff CA, Schwartz J, Bergman CM, Russell KS, Bender JR, Ruddle NH (1998) Lymphotoxin alpha3 induces chemokines and adhesion molecules: insight into the role of LT alpha in inflammation and lymphoid organ development. J Immunol 161:6853–6860PubMedGoogle Scholar
  23. 23.
    De Togni P, Goellner J, Ruddle NH, Streeter PR, Fick A, Mariathasan S, Smith SC, Carlson R, Shornick LP, Strauss-Schoenberger J et al (1994) Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science 264:703–707CrossRefPubMedGoogle Scholar
  24. 24.
    Drayton DL, Liao S, Mounzer RH, Ruddle NH (2006) Lymphoid organ development: from ontogeny to neogenesis. Nat Immunol 7:344–353CrossRefPubMedGoogle Scholar
  25. 25.
    Drayton DL, Ying X, Lee J, Lesslauer W, Ruddle NH (2003) Ectopic LT alpha beta directs lymphoid organ neogenesis with concomitant expression of peripheral node addressin and a HEV-restricted sulfotransferase. J Exp Med 197:1153–1163CrossRefPubMedGoogle Scholar
  26. 26.
    Erickson SL, de Sauvage FJ, Kikly K, Carver-Moore K, Pitts-Meek S, Gillett N, Sheehan KC, Schreiber RD, Goeddel DV, Moore MW (1994) Decreased sensitivity to tumour-necrosis factor but normal T-cell development in TNF receptor-2-deficient mice. Nature 372:560–563CrossRefPubMedGoogle Scholar
  27. 27.
    Eugster HP, Muller M, Karrer U, Car BD, Schnyder B, Eng VM, Woerly G, Le Hir M, di Padova F, Aguet M et al (1996) Multiple immune abnormalities in tumor necrosis factor and lymphotoxin-alpha double-deficient mice. Int Immunol 8:23–36CrossRefPubMedGoogle Scholar
  28. 28.
    Fan L, Reilly CR, Luo Y, Dorf ME, Lo D (2000) Cutting edge: ectopic expression of the chemokine TCA4/SLC is sufficient to trigger lymphoid neogenesis. J Immunol 164:3955–3959PubMedGoogle Scholar
  29. 29.
    Fava RA, Notidis E, Hunt J, Szanya V, Ratcliffe N, Ngam-Ek A, De Fougerolles AR, Sprague A, Browning JL (2003) A role for the lymphotoxin/LIGHT axis in the pathogenesis of murine collagen-induced arthritis. J Immunol 171:115–126PubMedGoogle Scholar
  30. 30.
    Fu YX, Chaplin DD (1999) Development and maturation of secondary lymphoid tissues. Annu Rev Immunol 17:399–433CrossRefPubMedGoogle Scholar
  31. 31.
    Fu YX, Molina H, Matsumoto M, Huang G, Min J, Chaplin DD (1997) Lymphotoxin-alpha (LTalpha) supports development of splenic follicular structure that is required for IgG responses. J Exp Med 185:2111–2120CrossRefPubMedGoogle Scholar
  32. 32.
    Futterer A, Mink K, Luz A, Kosco-Vilbois MH, Pfeffer K (1998) The lymphotoxin beta receptor controls organogenesis and affinity maturation in peripheral lymphoid tissues. Immunity 9:59–70CrossRefPubMedGoogle Scholar
  33. 33.
    Gommerman JL, Browning JL (2003) Lymphotoxin/light, lymphoid microenvironments and autoimmune disease. Nat Rev Immunol 3:642–655CrossRefPubMedGoogle Scholar
  34. 34.
    Gommerman JL, Giza K, Perper S, Sizing I, Ngam-Ek A, Nickerson-Nutter C, Browning JL (2003) A role for surface lymphotoxin in experimental autoimmune encephalomyelitis independent of LIGHT. J Clin Invest 112:755–767PubMedGoogle Scholar
  35. 35.
    Grabner R, Lotzer K, Dopping S, Hildner M, Radke D, Beer M, Spanbroek R, Lippert B, Reardon CA, Getz GS et al (2009) Lymphotoxin beta receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE-/- mice. J Exp Med 206:233–248CrossRefPubMedGoogle Scholar
  36. 36.
    Granger GA (1972) Lymphokines–the mediators of cellular immunity. Ser Haematol 5:8–40PubMedGoogle Scholar
  37. 37.
    Granger GA, Shacks SJ, Williams TW, Kolb WP (1969) Lymphocyte in vitro cytotoxicity: specific release of lymphotoxin-like materials from tuberculin-sensitive lymphoid cells. Nature 221:1155–1157CrossRefPubMedGoogle Scholar
  38. 38.
    Granger GA, Williams TW (1968) Lymphocyte cytotoxicity in vitro: activation and release of a cytotoxic factor. Nature 218:1253–1254CrossRefPubMedGoogle Scholar
  39. 39.
    Gray PW, Aggarwal BB, Benton CV, Bringman TS, Henzel WJ, Jarrett JA, Leung DW, Moffat B, Ng P, Svedersky LP et al (1984) Cloning and expression of cDNA for human lymphotoxin, a lymphokine with tumour necrosis activity. Nature 312:721–724CrossRefPubMedGoogle Scholar
  40. 40.
    Greten FR, Eckmann L, Greten TF, Park JM, Li ZW, Egan LJ, Kagnoff MF, Karin M (2004) IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118:285–296CrossRefPubMedGoogle Scholar
  41. 41.
    Greten FR, Karin M (2004) The IKK/NF-kappaB activation pathway-a target for prevention and treatment of cancer. Cancer Lett 206:193–199CrossRefPubMedGoogle Scholar
  42. 42.
    Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70CrossRefPubMedGoogle Scholar
  43. 43.
    Haybaeck J, Zeller N, Wolf MJ, Weber A, Wagner U, Kurrer MO, Bremer J, Iezzi G, Graf R, Clavien PA et al (2009) A lymphotoxin-driven pathway to hepatocellular carcinoma. Cancer Cell 16:295–308CrossRefPubMedGoogle Scholar
  44. 44.
    Hehlgans T, Stoelcker B, Stopfer P, Muller P, Cernaianu G, Guba M, Steinbauer M, Nedospasov SA, Pfeffer K, Mannel DN (2002) Lymphotoxin-beta receptor immune interaction promotes tumor growth by inducing angiogenesis. Cancer Res 62:4034–4040PubMedGoogle Scholar
  45. 45.
    Heikenwalder M, Prinz M, Zeller N, Lang KS, Junt T, Rossi S, Tumanov A, Schmidt H, Priller J, Flatz L et al (2008) Overexpression of lymphotoxin in T cells induces fulminant thymic involution. Am J Pathol 172:1555–1570CrossRefPubMedGoogle Scholar
  46. 46.
    Heikenwalder M, Zeller N, Seeger H, Prinz M, Klohn PC, Schwarz P, Ruddle NH, Weissmann C, Aguzzi A (2005) Chronic lymphocytic inflammation specifies the organ tropism of prions. Science 307:1107–1110CrossRefPubMedGoogle Scholar
  47. 47.
    Karin M (2008) The IkappaB kinase – a bridge between inflammation and cancer. Cell Res 18:334–342CrossRefPubMedGoogle Scholar
  48. 48.
    Kawashima H (2006) Roles of sulfated glycans in lymphocyte homing. Biol Pharm Bull 29:2343–2349CrossRefPubMedGoogle Scholar
  49. 49.
    Kawashima H, Hirakawa J, Tobisawa Y, Fukuda M, Saga Y (2009) Conditional gene targeting in mouse high endothelial venules. J Immunol 182:5461–5468CrossRefPubMedGoogle Scholar
  50. 50.
    Keats JJ, Fonseca R, Chesi M, Schop R, Baker A, Chng WJ, Van Wier S, Tiedemann R, Shi CX, Sebag M et al (2007) Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma. Cancer Cell 12:131–144CrossRefPubMedGoogle Scholar
  51. 51.
    Kolb WP, Granger GA (1968) Lymphocyte in vitro cytotoxicity: characterization of human lymphotoxin. Proc Natl Acad Sci U S A 61:1250–1255CrossRefPubMedGoogle Scholar
  52. 52.
    Koni PA, Sacca R, Lawton P, Browning JL, Ruddle NH, Flavell RA (1997) Distinct roles in lymphoid organogenesis for lymphotoxins alpha and beta revealed in lymphotoxin beta-deficient mice. Immunity 6:491–500CrossRefPubMedGoogle Scholar
  53. 53.
    Kratz A, Campos-Neto A, Hanson MS, Ruddle NH (1996) Chronic inflammation caused by lymphotoxin is lymphoid neogenesis. J Exp Med 183:1461–1472CrossRefPubMedGoogle Scholar
  54. 54.
    Kuprash DV, Qin Z, Ito D, Grivennikov SI, Abe K, Drutskaya LN, Blankenstein T, Nedospasov SA (2008) Ablation of TNF or lymphotoxin signaling and the frequency of spontaneous tumors in p53-deficient mice. Cancer Lett 268:70–75CrossRefPubMedGoogle Scholar
  55. 55.
    Kuprash DV, Tumanov AV, Liepinsh DJ, Koroleva EP, Drutskaya MS, Kruglov AA, Shakhov AN, Southon E, Murphy WJ, Tessarollo L et al (2005) Novel tumor necrosis factor-knockout mice that lack Peyer’s patches. Eur J Immunol 35:1592–1600CrossRefPubMedGoogle Scholar
  56. 56.
    Laxton R, Pearce E, Kyriakou T, Ye S (2005) Association of the lymphotoxin-alpha gene Thr26Asn polymorphism with severity of coronary atherosclerosis. Genes Immun 6:539–541CrossRefPubMedGoogle Scholar
  57. 57.
    Lee SH, Park SG, Lim SO, Jung G (2005) The hepatitis B virus X protein up-regulates lymphotoxin alpha expression in hepatocytes. Biochim Biophys Acta 1741:75–84PubMedGoogle Scholar
  58. 58.
    Lo JC, Wang Y, Tumanov AV, Bamji M, Yao Z, Reardon CA, Getz GS, Fu YX (2007) Lymphotoxin beta receptor-dependent control of lipid homeostasis. Science 316:285–288CrossRefPubMedGoogle Scholar
  59. 59.
    Lorenz RG, Chaplin DD, McDonald KG, McDonough JS, Newberry RD (2003) Isolated lymphoid follicle formation is inducible and dependent upon lymphotoxin-sufficient B lymphocytes, lymphotoxin beta receptor, TNF receptor I function. J Immunol 170:5475–5482PubMedGoogle Scholar
  60. 60.
    Lowes KN, Croager EJ, Abraham LJ, Olynyk JK, Yeoh GC (2003) Upregulation of lymphotoxin beta expression in liver progenitor (oval) cells in chronic hepatitis C. Gut 52:1327–1332CrossRefPubMedGoogle Scholar
  61. 61.
    Luedde T, Beraza N, Kotsikoris V, van Loo G, Nenci A, De Vos R, Roskams T, Trautwein C, Pasparakis M (2007) Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell 11:119–132CrossRefPubMedGoogle Scholar
  62. 62.
    Lukashev M, LePage D, Wilson C, Bailly V, Garber E, Lukashin A, Ngamek, A., Zeng W, Allaire N, Perrin S et al (2006) Targeting the lymphotoxin-beta receptor with agonist antibodies as a potential cancer therapy. Cancer Res 66:9617–9624CrossRefPubMedGoogle Scholar
  63. 63.
    Luther SA, Bidgol A, Hargreaves DC, Schmidt A, Xu Y, Paniyadi J, Matloubian M, Cyster JG (2002) Differing activities of homeostatic chemokines CCL19, CCL21, CXCL12 in lymphocyte and dendritic cell recruitment and lymphoid neogenesis. J Immunol 169:424–433PubMedGoogle Scholar
  64. 64.
    Luther SA, Lopez T, Bai W, Hanahan D, Cyster JG (2000) BLC expression in pancreatic islets causes B cell recruitment and lymphotoxin-dependent lymphoid neogenesis. Immunity 12:471–481CrossRefPubMedGoogle Scholar
  65. 65.
    Maeda S, Kamata H, Luo JL, Leffert H, Karin M (2005) IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 121:977–990CrossRefPubMedGoogle Scholar
  66. 66.
    Mantovani A, Pierotti MA (2008) Cancer and inflammation: a complex relationship. Cancer Lett 267:180–181CrossRefPubMedGoogle Scholar
  67. 67.
    Markey KA, Burman AC, Banovic T, Kuns RD, Raffelt NC, Rowe V, Olver SD, Don AL, Morris ES, Pettit AR et al (2010) Soluble lymphotoxin is an important effector molecule in GVHD and GVL. Blood 115:122–132CrossRefPubMedGoogle Scholar
  68. 68.
    Martin AP, Coronel EC, Sano G, Chen SC, Vassileva G, Canasto-Chibuque C, Sedgwick JD, Frenette PS, Lipp M, Furtado GC, Lira SA (2004) A novel model for lymphocytic infiltration of the thyroid gland generated by transgenic expression of the CC chemokine CCL21. J Immunol 173:4791–4798PubMedGoogle Scholar
  69. 69.
    Martins VC, Boehm T, Bleul CC (2008) Ltbetar signaling does not regulate Aire-dependent transcripts in medullary thymic epithelial cells. J Immunol 181:400–407PubMedGoogle Scholar
  70. 70.
    Matsumoto M, Hsieh TY, Zhu N, VanArsdale T, Hwang SB, Jeng KS, Gorbalenya AE, Lo SY, Ou JH, Ware CF, Lai MM (1997) Hepatitis C virus core protein interacts with the cytoplasmic tail of lymphotoxin-beta receptor. J Virol 71:1301–1309PubMedGoogle Scholar
  71. 71.
    Muller U, Jongeneel CV, Nedospasov SA, Lindahl KF, Steinmetz M (1987) Tumour necrosis factor and lymphotoxin genes map close to H-2D in the mouse major histocompatibility complex. Nature 325:265–267CrossRefPubMedGoogle Scholar
  72. 72.
    Ng TI, Mo H, Pilot-Matias T, He Y, Koev G, Krishnan P, Mondal R, Pithawalla R, He W, Dekhtyar T et al (2007) Identification of host genes involved in hepatitis C virus replication by small interfering RNA technology. Hepatology 45:1413–1421CrossRefPubMedGoogle Scholar
  73. 73.
    Ngo VN, Korner H, Gunn MD, Schmidt KN, Riminton DS, Cooper MD, Browning JL, Sedgwick JD, Cyster JG (1999) 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. J Exp Med 189:403–412CrossRefPubMedGoogle Scholar
  74. 74.
    Or YY, Chung GT, To KF, Chow C, Choy KW, Tong CY, Leung AW, Hui AB, Tsao SW, Ng HK et al (2009) Identification of a novel 12p13.3 amplicon in nasopharyngeal carcinoma. J PatholGoogle Scholar
  75. 75.
    Pasparakis M, Alexopoulou L, Episkopou V, Kollias G (1996) Immune and inflammatory responses in TNF alpha-deficient mice: a critical requirement for TNF alpha in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response J Exp Med 184:1397–1411CrossRefPubMedGoogle Scholar
  76. 76.
    Pfeffer K, Matsuyama T, Kundig TM, Wakeham A, Kishihara K, Shahinian A, Wiegmann K, Ohashi PS, Kronke M, Mak TW (1993) Mice deficient for the 55 kd tumor necrosis factor receptor are resistant to endotoxic shock, yet succumb to L. monocytogenes infection. Cell 73:457–467CrossRefPubMedGoogle Scholar
  77. 77.
    Picarella DE, Kratz A, Li CB, Ruddle NH, Flavell RA (1992) Insulitis in transgenic mice expressing tumor necrosis factor beta (lymphotoxin) in the pancreas. Proc Natl Acad Sci U S A 89:10036–10040CrossRefPubMedGoogle Scholar
  78. 78.
    Picarella DE, Kratz A, Li CB, Ruddle NH, Flavell RA (1993) Transgenic tumor necrosis factor (TNF)-alpha production in pancreatic islets leads to insulitis, not diabetes. Distinct patterns of inflammation in TNF-alpha and TNF-beta transgenic mice. Journal of Immunology 150:4136–4150Google Scholar
  79. 79.
    Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, Gutkovich-Pyest E, Urieli-Shoval S, Galun E, Ben-Neriah Y (2004) NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 431:461–466CrossRefPubMedGoogle Scholar
  80. 80.
    Plant SR, Iocca HA, Wang Y, Thrash JC, O’Connor BP, Arnett HA, Fu YX, Carson MJ, Ting JP (2007) Lymphotoxin beta receptor (Lt betaR): dual roles in demyelination and remyelination and successful therapeutic intervention using Lt betaR-Ig protein. J Neurosci 27:7429–7437CrossRefPubMedGoogle Scholar
  81. 81.
    Puglielli MT, Browning JL, Brewer AW, Schreiber RD, Shieh WJ, Altman JD, Oldstone MB, Zaki SR, Ahmed R (1999) Reversal of virus-induced systemic shock and respiratory failure by blockade of the lymphotoxin pathway. Nat Med 5:1370–1374CrossRefPubMedGoogle Scholar
  82. 82.
    Rennert PD, Browning JL, Mebius R, Mackay F, Hochman PS (1996) Surface lymphotoxin alpha/beta complex is required for the development of peripheral lymphoid organs. J Exp Med 184:1999–2006CrossRefPubMedGoogle Scholar
  83. 83.
    Ruddell RG, Knight B, Tirnitz-Parker JE, Akhurst B, Summerville L, Subramaniam VN, Olynyk JK, Ramm GA (2009) Lymphotoxin-beta receptor signaling regulates hepatic stellate cell function and wound healing in a murine model of chronic liver injury. Hepatology 49:227–239CrossRefPubMedGoogle Scholar
  84. 84.
    Ruddle NH, Waksman BH (1967) Cytotoxic effect of lymphocyte-antigen interaction in delayed hypersensitivity. Science 157:1060–1062CrossRefPubMedGoogle Scholar
  85. 85.
    Ruddle NH, Waksman BH (1968) Cytotoxicity mediated by soluble antigen and lymphocytes in delayed hypersensitivity. 3. Analysis of mechanism. J Exp Med 128:1267–1279CrossRefPubMedGoogle Scholar
  86. 86.
    Sayi A, Kohler E, Hitzler I, Arnold I, Schwendener R, Rehrauer H, Muller A (2009) The CD4+ T cell-mediated IFN-gamma response to Helicobacter infection is essential for clearance and determines gastric cancer risk. J Immunol 182:7085–7101CrossRefPubMedGoogle Scholar
  87. 87.
    Senftleben U, Cao Y, Xiao G, Greten FR, Krähn G, Bonizzi G, Chen Y, Hu Y, Fong A, Sun SC, Karin M (2001) Activation by IKKalpha of a second, evolutionary conserved, NF-kappa B signaling pathway. Science 293:1495–1499CrossRefPubMedGoogle Scholar
  88. 88.
    Schreyer SA, Vick CM, LeBoeuf RC (2002) Loss of lymphotoxin-alpha but not tumor necrosis factor-alpha reduces atherosclerosis in mice. J Biol Chem 277:12364–12368CrossRefPubMedGoogle Scholar
  89. 89.
    Subrata LS, Lowes KN, Olynyk JK, Yeoh GC, Quail EA, Abraham LJ (2005) 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. Liver Int 25:633–646CrossRefPubMedGoogle Scholar
  90. 90.
    Tumanov AV, Christiansen PA, Fu YX (2007) The role of lymphotoxin receptor signaling in diseases. Curr Mol Med 7:567–578CrossRefPubMedGoogle Scholar
  91. 91.
    Tumanov AV, Koroleva EP, Christiansen PA, Khan MA, Ruddy MJ, Burnette B, Papa S, Franzoso G, Nedospasov SA, Fu YX, Anders RA (2009) T cell-derived lymphotoxin regulates liver regeneration. Gastroenterology 136:694–704 e694CrossRefPubMedGoogle Scholar
  92. 92.
    Vainer GW, Pikarsky E, Ben-Neriah Y (2008) Contradictory functions of NF-kappaB in liver physiology and cancer. Cancer Lett 267:182–188CrossRefPubMedGoogle Scholar
  93. 93.
    Vallabhapurapu S, Karin M (2009) Regulation and function of NF-kappaB transcription factors in the immune system. Annu Rev Immunol 27:693–733CrossRefPubMedGoogle Scholar
  94. 94.
    Ware CF (2005) Network communications: lymphotoxins, LIGHT, and TNF. Annu Rev Immunol 23:787–819CrossRefPubMedGoogle Scholar
  95. 95.
    Williams TW, Granger GA (1968) Lymphocyte in vitro cytotoxicity: lymphotoxins of several mammalian species. Nature 219:1076–1077CrossRefPubMedGoogle Scholar
  96. 96.
    Zhou P, Fang X, McNally BA, Yu P, Zhu M, Fu YX, Wang L, Liu Y, Zheng P (2009) Targeting lymphotoxin-mediated negative selection to prevent prostate cancer in mice with genetic predisposition. Proc Natl Acad Sci U S A 106:17134–17139CrossRefPubMedGoogle Scholar
  97. 97.
    Zhu N, Khoshnan A, Schneider R, Matsumoto M, Dennert G, Ware C, Lai MM (1998) Hepatitis C virus core protein binds to the cytoplasmic domain of tumor necrosis factor (TNF) receptor 1 and enhances TNF-induced apoptosis. J Virol 72:3691–3697PubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Monika Julia Wolf
    • 1
  • Gitta Maria Seleznik
    • 1
  • Mathias Heikenwalder
    • 2
  1. 1.Department of PathologyInstitute of Neuropathology, University Hospital ZurichZurichSwitzerland
  2. 2.Department of PathologyUniversity Hospital ZurichZurichSwitzerland

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