Immunologic Research

, Volume 11, Issue 2, pp 81–90 | Cite as

Tumor necrosis factor receptors-structure and function

  • Joachim Rothe
  • Gisela Gehr
  • Hansruedi Loetscher
  • Werner Lesslauer
TNF Receptors


Tumor necrosis factors (TNFs) have been a focus of research for well over a decade now. The identification and recent molecular cloning of two different types of cell-surface TNF receptors will shed further light on the mode of action of these pleiotropic cytokines. In the present article, we summarize the data on the biochemistry and structure of the receptors and focus on the molecular cloning of the respective cDNAs. The nucleotide sequences of the receptor genes revealed that both TNF receptors belong to the still growing nerve growth factor receptor gene family. The function and orgin of TNF inhibitory proteins as well as receptor-mediated signal transduction are discussed.

Key Words

Tumor necrosis factor, receptors and inhibitory proteins Nerve growth factor receptor family Cytokines 


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  1. 1.
    Coley WB: The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases. Am J Med Sci 1893;105:487.CrossRefGoogle Scholar
  2. 2.
    Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B: An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci USA 1975;72:3666.PubMedCrossRefGoogle Scholar
  3. 3.
    Old LJ: Tumor necrosis factor (TNF). Science 1985;230:630.PubMedCrossRefGoogle Scholar
  4. 4.
    Beutler B, Cerami A: The biology of cachectin/TNF—a primary mediator of the host response. Ann Rev Immunol 1989;7:625.Google Scholar
  5. 5.
    Tracey K, Fong Y, Hesse DG, Manogue KR, Lee AT, Kuo GC, Lowry SF, Cerami A: Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteriaemia. Nature 1987;330:662.PubMedCrossRefGoogle Scholar
  6. 6.
    Mustafa MM, Ramilo O, Mertsola J, Risser RC, Beutler B, Hansen EJ, McCracken GH: Modulation of in-flammation and cachectin activity in relation to treatment of experimentalHemophilus influenzae type b meningitis. J Infect Dis 1989;160:818.PubMedGoogle Scholar
  7. 7.
    Nedwin GE, Naylor SL, Sakaguchi AY, Smith D, Jarett-Nedwin J, Pennica D, Goeddel DV, Gray PW: Human lymphotoxin and tumor necrosis factor genes: Structure, homology and chromosomal location. Nucleic Acids Res 1985;13:6361.PubMedCrossRefGoogle Scholar
  8. 8.
    Eck MJ, Sprang SR: The structure of tumor necrosis factor-alpha at 2.6 Å resolution. Implications for receptor binding. J Biol Chem 1989;264:17595.PubMedGoogle Scholar
  9. 9.
    Jones EY, Stuart DI, Walker NPC: Structure of tumor necrosis factor. Nature 1989;338:225.PubMedCrossRefGoogle Scholar
  10. 10.
    Schoenfeld HJ, Poeschl B, Frey JR, Loetscher H, Hunziker W, Lustig A, Zulauf M: Efficient purification of recombinant human tumor necrosis factor beta fromE. coli yields biologically active protein with a trimeric structure that binds to both TNF receptors. J Biol Chem 1991;266:3863.PubMedGoogle Scholar
  11. 11.
    Loetscher HR, Schlaeger EJ, Lahm HW, Pan YCE, Lesslauer W, Brockhaus M: Purification and partial amino acid sequence analysis of two distinct tumor necrosis factor receptors from HL60 cells. J Biol Chem 1990;265:20131.PubMedGoogle Scholar
  12. 12.
    Loetscher HR, Pan YE, Lahm HW, Gentz R, Brockhaus M, Tabuchi H, Lesslauer W: Molecular cloning and expression of the 55kd tumor necrosis factor receptor. Cell 1990;61:351.PubMedCrossRefGoogle Scholar
  13. 13.
    Dembic Z, Loetscher HR, Gubler U, Pan YCE, Lahm HW, Gentz R, Brockhaus M, Lesslauer W: Two human TNF receptors have similar extracellular, but distinct intracellular, domain sequences. Cytokine 1990; 2:231.PubMedCrossRefGoogle Scholar
  14. 14.
    Schall TJ, Lewis M, Koller KJ, Lee A, Rice GC, Wong GHW, Gatanaga T, Granger GA, Lentz R, Raab H, Kohr WJ, Goeddel DV: Molecular cloning and expression of a receptor for human tumor necrosis factor. Cell 1990;61:361.PubMedCrossRefGoogle Scholar
  15. 15.
    Smith CA, Davis T, Anderson D, Solam L, Beckmann MP, Jerzy R, Dower SK, Cosman D, Goodwin RG: A receptor for tumor necrosis factor defines an unusual family of cellular and viral proteins. Science 1990;248:1019.PubMedCrossRefGoogle Scholar
  16. 16.
    Heller RA, Song K, Onasch MA, Fischer WH, Chang D, Ringold GM: Complementary DNA cloning of a receptor for tumor necrosis factor and demonstration of a shed form of the receptor. Proc Natl Acad Sci USA 1990;87:6151.PubMedCrossRefGoogle Scholar
  17. 17.
    Kohno T, Brewer MT, Baker SL, Schwartz PE, King MW, Hale KK, Squires CH, Thompson RC, Vanice JL: A second tumor necrosis factor receptor gene product can shed a naturally occurring tumor necrosis factor inhibitor. Proc Natl Acad Sci USA 1990;87:8331.PubMedCrossRefGoogle Scholar
  18. 18.
    Nophar Y, Kemper O, Brakebusch C, Engelmann H, Zwang R, Aderka D, Holtmann H, Wallach D: Soluble forms of tumor necrosis factor receptors (TNF-Rs). The cDNA for the type I TNF-R cloned using amino acid sequence data of its soluble form encodes both the cell surface and a soluble form of the receptor. EMBO J 1990;9:3269.PubMedGoogle Scholar
  19. 19.
    Himmler A, Maurerfogy I, Kronke M, Scheurich P, Pfizenmaier K, Lantz M, Olsson I, Hauptmann C, Stratowa C, Adolf GR: Molecular cloning and expression of human and rat tumor necrosis factor receptor chain (p60) and its soluble derivative—tumor necrosis factor binding protein DNA. Cell Biol 1990;9:705.Google Scholar
  20. 20.
    Gray PW, Barrett K, Chantry D, Turner M, Feldmann M: Cloning of human tumor necrosis factor cDNA and expression of recombinant soluble TNF-binding protein, Proc Natl Acad Sci USA 1990;87:7380.PubMedCrossRefGoogle Scholar
  21. 21.
    Lewis M, Tartaglia LA, Lee A, Bennett GL, Rice GC, Wong GHW, Chen EY, Goeddel DV: Cloning and expression of cDNAs for two distinct murine tumor necrosis factor receptors demonstrate one receptor is species specific. Proc. Natl Acad Sci USA 1991;88:2830.PubMedCrossRefGoogle Scholar
  22. 22.
    Rothe JG, Brockhaus M, Gentz R, Lesslauer W: Molecular cloning and expression of the mouse TNF receptor type b. Immunogenetics, in press.Google Scholar
  23. 23.
    Loetscher HR, Brockhaus M, Dembic Z, Gentz R, Gubler U, Hohmann HP, Lahm HW, van Loon APGM, Pan YCE, Schlaeger FJ, Steinmetz M, Tabuchi H, Lesslauer W: Two distinct tumor necrosis factor receptors—members of a new cytokine receptor gene family; in Maclean (ed). Oxford Survey on Eucaryotic Genes. Oxford, Oxford University Press. 1991.Google Scholar
  24. 24.
    Hohmann H, Remy R, Brockhaus M, van Loon APGM: Two different cell types have different major receptors for human tumor necrosis factor (TNF alpha). J Biol Chem 1989;264:14927.PubMedGoogle Scholar
  25. 25.
    Brockhaus M, Schoenfeld HJ, Schlaeger FJ, Hunziker W, Lesslauer W, Loetscher HR: Identification of two types of tumor necrosis factor receptors on human cell lines by monoclonal antibodies. Proc Natl Acad Sci USA 1990;87:3127.PubMedCrossRefGoogle Scholar
  26. 26.
    Loetscher HR, Schlaeger EJ, Lahm HW, Pan YCE, Lesslauer W, Brockhaus M: Purification and partial amino acid sequence analysis of two distinct tumor necrosis factor receptors from HL60 cells. J Biol Chem 1990;265:20131.PubMedGoogle Scholar
  27. 27.
    Loetscher H: Purification and structural properties of two distinct TNF receptors on human cells; in Aggarwal, Vilcek (eds), Tumor necrosis factors—structure, function and mechanism of action: Marcel Dekker, New York, 1991.Google Scholar
  28. 28.
    Mallett S, Barclay AN: A new superfamily of cell surface proteins related to the nerve growth factor receptor. Immunol Today 1991;12:220.PubMedCrossRefGoogle Scholar
  29. 29.
    Rogers S, Wells R, Rechsteiner M: Amino acid sequences common to rapidly degraded proteins. The PEST hypothesis. Science 1986;234:364.PubMedCrossRefGoogle Scholar
  30. 30.
    Seckinger P, Isaaz S, Dayer JM: A human inhibitor of tumor necrosis factor alpha. J Exp Med 1988;167: 1511.PubMedCrossRefGoogle Scholar
  31. 31.
    Seckinger P, Isaaz S, Dayer JM: Purification and biologic characterisation of a specific tumor necrosis factor alpha inhibitor. J Biol Chem 1989;264:11966.PubMedGoogle Scholar
  32. 32.
    Olsson I, Lantz M, Nilsson E, Peetre C, Thysell H, Grubb A, Adolf G: Isolation and characterisation of a tumor necrosis factor binding protein from urine. Eur J Haematol 1989;42:270.PubMedGoogle Scholar
  33. 33.
    Peetre C, Thyseel H, Grubb A, Olson I: A tumor necrosis factor binding protein is present in human biological fluids. Eur J Haematol 1988; 41:414.PubMedGoogle Scholar
  34. 34.
    Engelmann H, Aderka D, Rubinstein M, Rotman D, Wallach D: A tumor necrosis factor-binding protein purified to homogeneity from human urineprotects cells from tumor necrosis factor toxicity. J Biol Chem 1989;264:11974.PubMedGoogle Scholar
  35. 35.
    Engelmann H, Novick D, Wallach D: Two tumor necrosis factor-binding proteins purified from human urine. Evidence for immunological cross-reactivity with cell surface tumor necrosis factor receptors. J Biol Chem 1990;265:1531.PubMedGoogle Scholar
  36. 36.
    Olsson I, Lantz M, Nilsson E, Peetre C, Thysell H, Grubb A, Adolf G: Isolation and characterisation of a tumor necrosis factor binding protein from urine. Eur J Haematol 1989;42:270.PubMedCrossRefGoogle Scholar
  37. 37.
    Seckinger P, Vey E, Turcatti G, Wingfield P, Dayer JM: Tumor necrosis factor inhibitor. Purification NH2-terminal amino acid sequence and evidence for anti-inflammatory and immunomodulatory activities. Eur J Immunol 1990;20:1167.PubMedCrossRefGoogle Scholar
  38. 38.
    Digel W, Porzsolt F, Lesslauer W, Brockhaus M: Evidence for soluble receptors for tumor necrosis factor in the serum of cancer patients—high levels in B-cell malignancies, submitted.Google Scholar
  39. 39.
    Gatanaga T, Hwang C, Kohr W, Capuccini F, Lucci JA, Jeffes EWB, Lentz R, Tomich J, Yamamoto RS, Granger GA: Purification and characterisation of an inhibitor (soluble tumor necrosis factor receptor) for tumor necrosis factor and lymphotoxin obtained from the serum ultrafiltrates of human cancer patients. Proc Natl Acad Sci USA 1990;87:8781.PubMedCrossRefGoogle Scholar
  40. 40.
    Lesslauer W, Tabuchi H, Gentz R, Schlaeger EJ, Brockhaus M, Grau G, Piguet PF, Pointaire P, Vassalli P, Loetscher H: Bioactivity of recombinant human TNF receptor fragments. J Cell Biochem 1991; 15F(suppl):115.Google Scholar
  41. 41.
    Loetscher HR, Gentz R, Zulauf M, Lustig A, Tabuchi H, Schlaeger EJ, brockhaus M, Gallati H, Manneberg M, Lesslauer W: Recombinant 55kDa TNF receptor. Stoichiometry of binding to TNFalpha and TNFbeta and inhibition of TNF activity. J Biol Chem, in press.Google Scholar
  42. 42.
    Hohmann HP, Remy R, Poeschl B, van Loon APGM: Tumor necrosis factors-alpha and-beta bind to the same two types of tumor necrosis factor receptors and maximally activate the transcription factor NK-kB at low receptor occupancy and within minutes after receptor binding, J Biol Chem 1990;265:15183.PubMedGoogle Scholar
  43. 43.
    Engelmann H, Holtmann H, Brakebusch C, Avni SY, Sarov I, Nophar Y, Hadas E, Leitner O, Wallach D: Antibodies to a soluble form of a tumor necrosis factor (TNF) receptor have TNF-like activity. J Biol Chem 1990;265:14497.PubMedGoogle Scholar
  44. 44.
    Hibi M, Murakami M, Saito M, Hirano T, Taga T, Kishimoto T: Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell 1990;63:1149.PubMedCrossRefGoogle Scholar
  45. 45.
    Kobayashi N, Hamamoto Y, Yamamoto N, Ishii A, Yonehara M, Yonehara S: Anti-FAS monoclonal anti-body is cytocidal to human immunodeficiency virus-infected cells without augmenting viral replication. Proc Natl Acad Sci USA 1990; 87:9620.PubMedCrossRefGoogle Scholar
  46. 46.
    Brouckaert PG, Everaerdt B, Libert C, Takahashi N, Fiers W: Species specificity and involvement of other cytokines in endotoxic shock action of recombinant tumor necrosis factor in mice. Agents Actions 1989;26:196.PubMedCrossRefGoogle Scholar
  47. 47.
    Hohmann HP, Brockhaus M, Baeuerle PA, Remy R, Kolbeck R, van Loon APGM: Expression of the types A and B tumor necrosis factor (TNF) receptors is independently regulated and both receptors mediate activation of the transcription factor NF-kB. TNFalpha is not needed for induction of a biological effect via TNF receptors J Biol Chem 1990;265:22409.PubMedGoogle Scholar
  48. 48.
    Gehr G, Gentz R, Loetscher HR, Brockhaus M, Tabuchi H, Lesslauer W: TNF receptors alpha and beta (TNFRalpha, TNFRbeta) in human mononuclear cell activation, submitted.Google Scholar
  49. 49.
    Thoma B, Grell M, Pfizenmaier K, Scheurich P: Identification of a 60 kD tumor necrosis factor (TNF) receptor as the major signal transducing component in TNF responses. J Exp Med 1990;172:1019.PubMedCrossRefGoogle Scholar
  50. 50.
    Meichle A, Schuetze S, Hensel G, Brunsing D, Kroenke M: Protein kinase C-independent activation of nuclear factor kB by tumor necrosis factor. J Biol Chem 1990;265:8339.PubMedGoogle Scholar
  51. 51.
    Brenner DA, O'Hara M, Angel P, Chojkier M, Karin M: Prolonged activation of jun and collagenase genes by tumor necrosis factor alpha. Nature 1989;337:661.PubMedCrossRefGoogle Scholar
  52. 52.
    Harada H, Fujita T, Miyamoto M, Kimura Y, Maruyama M, Furia A, Miyata T, Taniguchi T: Structurally similar but functionally distinct factors IRF-1 and IRF-2 bind to the same regulatory elements of IFN and IFN-inducible genes. Cell 1989; 58:729.PubMedCrossRefGoogle Scholar
  53. 53.
    Zhang Y, Lin JX, Vilcek J: Interleukin 6 induction by tumor necrosis factor and interleukin 1 in human fibroblasts involves activation of a nuclear factor binding to a kB like sequence. Mol Cell Biol 1990;10:3818.PubMedGoogle Scholar
  54. 54.
    Ray A, Sassone-Corsi P, Sehgal P: A multiple cytokine-and second messenger-responsive element in the enhancer of the human interleukin-6 gene. Similarities with c-fos gene regulation. Mol Cell Biol 1989;9:5537.PubMedGoogle Scholar
  55. 55.
    Akira S, Isshiki H, Sugita T, Tanabe O, Kinoshita S, Nishio Y, Nakajima T, Hirano T, Kishimoto T: A nuclear factor for IL-6 expression (NFIL6) is a member of a C/EBP family. EMBO J 1990;9:1897.PubMedGoogle Scholar
  56. 56.
    Schuetze S, Scheurich P, Pfizenmaier K, Kroenke M: Tumor necrosis factor signal transduction. Tumor specific serine phosphorylation of a 26 kDa cytosolic protein. J Biol Chem 1989;264:3562.Google Scholar
  57. 57.
    Donato NJ, Gallick GE, Steck PA, Rosenblum MG: Tumor necrosis factor modulates epidermal growth factor receptor phosphorylation and kinase activity in human tumor cells. Correlation with cytotoxicity. J Biol Chem 1989;264:20474.PubMedGoogle Scholar
  58. 58.
    Marino M, Pfeffer LM, Guidon PT, Donner DB: Tumor necrosis factor induces phosphorylation of a 28 kDa mRNA cap-binding protein in human cervical carcinoma cells. Proc Natl Acad Sci USA 1989;86: 8417PubMedCrossRefGoogle Scholar
  59. 59.
    Kohno M, Nishizawa N, Tsujimoto M, Nomoto H: Mitogenic signalling pathway of tumor necrosis factor involves the rapid tyrosine phosphorylation of 41'000 Mr and 43'000 Mr cytosol proteins. Biochem J 1990; 267:91.PubMedGoogle Scholar
  60. 60.
    Shiroo M, Matsushima K: Enhanced phosphorylation of 65 and 74 kDa proteins by tumor necrosis factor and interleukin 1 in human peripheral blood mononuclear cells. Cytokine 1990;2:13.PubMedCrossRefGoogle Scholar
  61. 61.
    Bird TA, Saklatvala J: IL-1 and TNF transmodulate epidermal growth factor receptors by a protein kinase C-independent mechanism. J Immunol 1989;142:126.PubMedGoogle Scholar
  62. 62.
    Hohmann HP, Remy R, Schneidereit C, van Loon APGM: Cyclic AMP independent activation of the transcription factor NF-kB in HL60 cells by tumor necrosis factors alpha and beta. Mol Cell Biol 1991;11: 2315.PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 1992

Authors and Affiliations

  • Joachim Rothe
    • 1
  • Gisela Gehr
    • 1
  • Hansruedi Loetscher
    • 1
  • Werner Lesslauer
    • 1
  1. 1.F. Hoffmann-La Roche, Ltd.BaselSwitzerland

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