Surgery Today

, Volume 24, Issue 3, pp 197–202 | Cite as

The role of tumor necrosis factor receptors in cell signaling and the significance of soluble form levels in the serum

  • Yasuhito Abe
  • Yuji Watanabe
  • Shigeru Kimura
Review Article


Two types of tumor necrosis factor membrane receptors (TNF-R) have been identified, namely 55 and 75 kDa TNF-R. Soluble forms of these receptors are present in the human serum. Recent findings on the role of these two TNF-R in biological cell signaling and the clinical significance of the serum levels of soluble TNF-R (sTNF-R) were reviewed. It is not the uptake of TNF molecules into cells but rather the molecular capping of TNF-R on the cell membrane that initiates the biological activity of TNF. The 55 kDa TNF-R mediates major bioactivities of TNF, while the significance of 75 kDa TNF-R remains unclear. We herein suggest a new concept of the role of these two TNF-R: The 75 kDa TNF-R signal appeared to enhance that of 55 kDa TNF-R in the induction of ICAM-1 expression on HL-60 human promyelocytic leukemic cells. High serum levels of sTNF-R are reported in patients with malignancy, endotoxin shock, pneumonia, and autoimmune diseases. However, the source of elevated serum sTNF-R remains unclear. Studies on the clinical usefulness of serum sTNF-R levels as cancer and inflammation markers are now being carried out.

Key Words

tumor necrosis factor receptor signaling serum level 


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  1. 1.
    Van Ostade X, Vandenabeele P, Everaerdt B, Loetscher H, Gentz R, Brockhaus M, Lesslauer W, Tavernier J, Brouckaert P, Fiers W (1993) Human TNF mutants with selective activity on the p55 TNF receptor. Nature 361:266–269PubMedGoogle Scholar
  2. 2.
    Old LJ (1987) Tumor necrosis factor. Another chapter in the long history of endotoxin. Nature 330:602–603PubMedGoogle Scholar
  3. 3.
    Sugarman BJ, Aggarwal BB, Hass PE, Figari IS, Palladino MA, Shepard HM (1985) Recombinant human tumor necrosis factor-α: Effects on proliferation of normal and transformed cells in vitro. Science 230:943–945PubMedGoogle Scholar
  4. 4.
    Granger GA, Williams TW (1968) Lymphocyte cytotoxicity in vitro: Activation and release of a cytotoxic factor. Nature 218:1253–1254PubMedGoogle Scholar
  5. 5.
    Gray PW, Aggarwal BB, Benton CV, Bringman TS, Henzel WJ, Jarrett JA, Leung DW, Moffat B, Ng P, Svedersky LP, Palladino MA, Nedwin GE (1984) Cloning and expression of cDNA for human lymphotoxin, a lymphokine with tumour necrosis activity. Nature 312:721–724PubMedGoogle Scholar
  6. 6.
    Pennica D, Nedwin GE, Hayflick JS, Seeburg PH, Derynck R, Palladino MA, Kohr WJ, Aggarwal BB, Goeddel DV (1984) Human tumour necrosis factor: Precursor structure, expression, and homology to lymphotoxin. Nature 312:724–729PubMedGoogle Scholar
  7. 7.
    Yokota S, Geppert TD, Lipsky PE (1988) Enhancement of antigen- and mitogen-induced human T lymphocyte proliferation by tumor necrosis factor-α. J Immunol 140:531–536PubMedGoogle Scholar
  8. 8.
    Kehrl JH, Alvarez-Mon M, Delsing GA, Fauci AS (1987) Lymphotoxin is an important T cell-derived growth factor for human B cells. Science 238:1144–1146PubMedGoogle Scholar
  9. 9.
    Collins T, Lapierre LA, Fiers W, Strominge JL, Pober JS (1986) Recombinant human tumor necrosis factor increases mRNA levels and surface expression of HLA-A, B antigens in vascular endothelial cells and dermal fibroblasts in vitro. Proc Natl Acad Sci USA 83:446–450PubMedGoogle Scholar
  10. 10.
    Möst J, Schwaeble W, Drach J, Sommerauer A, Dierich MP (1992) Regulation of the expression of ICAM-1 on human monocytes and monocytic tumor cell lines. J Immunol 148:1635–1642PubMedGoogle Scholar
  11. 11.
    Shalaby MR, Aggarwal BB, Rinderknecht E, Sverdersky LP, Finkle BS, Palladino MA (1985) Activation of human polymorphonuclear neutrophil functions by interferon-γ and tumor necrosis factors. J Immunol 135:2069–2073PubMedGoogle Scholar
  12. 12.
    Kriegler M, Perez C, DeFay K, Albert I, Lu SD (1988) A novel form of TNF/cachectin is a cell surface cytotoxic transmembrane protein: Ramifications for the complex physiology of TNF. Cell 53:45–53PubMedGoogle Scholar
  13. 13.
    Abe Y, Miyake M, Horiuchi A, Kimura S, Hitsumoto Y (1991) Expression of membrane-associated lymphotoxin/tumor necrosis factor-β on human lymphokine-activated killer cells. Jpn J Cancer Res 82:23–26PubMedGoogle Scholar
  14. 14.
    Browning JL, Ngam-ek A, Lawton P, DeMarinis J, Tizard R, Chow EP, Hession C, O'Brine-Greco B, Foley SF, Ware CF (1993) Lymphotoxin β, a novel member of the TNF family that forms a heteromeric complex with lymphotoxin on the cell surface. Cell 72:847–856PubMedGoogle Scholar
  15. 15.
    Porter AG (1990) Human tumour necrosis factors-α and- β: Differences in their structure, expression, and biological properties. FEMS Microbiol Immunol 64:193–200Google Scholar
  16. 16.
    Alexander RB, Rosenberg SA (1991) Tumor necrosis factor: Clinical applications. In: DeVita VT, Hellman S, Rosenberg SA (eds) Biologic therapy of cancer. J.B. Lippincott, Philadelphia, pp 378–392Google Scholar
  17. 17.
    Brown TD, Goodman P, Fleming T, Macdonald JS, Hersh EM, Braun TJ (1991) A phase II Trial of recombinant tumor necrosis factor in patients with adenocarcinoma of the pancreas: A southwest oncology group study. J Immunotherapy 10:376–378Google Scholar
  18. 18.
    Skillings J, Wierzbicki R, Eisenhauer E, Venner P, Letendre F, Stewart D, Weinerman B (1992) A phase II study of recombinant tumor necrosis factor in renal cell carcinoma: A study of the national cancer institute of Canada clinical trials group. J Immunother 11:67–70PubMedGoogle Scholar
  19. 19.
    van der Schelling GP, Ijermans JNM, Kok TC, Scheringa M, Marquet RL, Splinter TAW, Jeekel J (1992) A phase I study of liver metastases with recombinant tumour necrosis factor. Eur J Cancer 28A:1073–1078PubMedGoogle Scholar
  20. 20.
    Andrews JS, Berger AE, Ware CF (1990) Characterization of the receptor for tumor necrosis factor (TNF) and lymphotoxin (LT) on human T lymphocytes. J Immunol 144:2582–2591PubMedGoogle Scholar
  21. 21.
    Sugarman BJ, Aggarwal BB, Hass PE, Figari IS, Palladino MA, Shepard HM (1985) Recombinant human tumor necrosis factora: Effects on the proliferation of normal and transformed cells in vitro. Science 230:943–945PubMedGoogle Scholar
  22. 22.
    Ware CF, Crowe PD, Vanarsdale TL, Andrews JL, Grayson MH, Jerzy R, Smith CA, Goodwin RG (1991) Tumor necrosis factor (TNF) receptor expression in T lymphocytes. J Immunol 147:4229–4238PubMedGoogle Scholar
  23. 23.
    Camussi G, Albano E, Tetta C, Bussolino F (1991) The molecular action of tumor necrosis factor-α. Eur J Biochem 202:3–14PubMedGoogle Scholar
  24. 24.
    Lewis M, Tartaglia LA, Lee A, Bennett GL, Rice GC, Wong GHW, Chen EY, Goeddel DV (1991) Cloning and expression of cDNAs for two distinct marine tumor necrosis factor receptors demonstrate one receptor is species specific. Proc Natl Acad Sci USA 88:2830–2834PubMedGoogle Scholar
  25. 25.
    Gray PW, Barrett K, Chantry D, Turner M, Feldmann M (1990) Cloning of human tumor necrosis factor (TNF) receptor cDNA and expression of recombinant soluble TNF-binding protein. Proc Natl Acad Sci USA 87:7380–7384PubMedGoogle Scholar
  26. 26.
    Kohno T, Brewer MT, Baker SL, Schwartz PE, King MW, Hale KK, Squires CH, Thompson RC, Vannice JL (1990) A second tumor necrosis factor receptor gene product can shed a naturally occurring tumor necrosis factor inhibitor. Proc Natl Acad Sci USA 87:8331–8335PubMedGoogle Scholar
  27. 27.
    Stauber GB, Aggarwal BB (1989) Characterization and affinity cross-linking of receptors for human recombinant lymphotoxin (tumor necrosis factor-β) on a human histiocytic lymphoma cell line, U-937. J Biol Chem 264:3573–3576PubMedGoogle Scholar
  28. 28.
    Hirano K, Yamamoto K, Kobayashi Y, Osawa T (1989) Characterization of specific high-affinity receptor for human lymphotoxin. J Biochem 105:120–126PubMedGoogle Scholar
  29. 29.
    Brockhaus M, Schoenfeld H-J, Schlaeger E-J, Hunziker W, LesslauerW, Loetscher H (1990) Identification of two types of tumor necrosis factor receptors on human cell lines by monoclonal antibodies. Proc Natl Acad Sci USA 87:3127–3131PubMedGoogle Scholar
  30. 30.
    Schall TJ, Lewis M, Koller KJ, Lee A, Rice GC, Wong GHW, Gatanaga T, Granger GA, Lentz R, Raab H, Kohr WJ, Goeddel DV (1990) Molecular cloning and expression of a receptor for tumor necrosis factor. Cell 61:361–370PubMedGoogle Scholar
  31. 31.
    Gatanaga T, Lentz R, Masunaka I, Tomich J, Jeffes EWB III, Baird M, Granger GA (1990) Identification of TNF-LT blocking factor(s) in the serum and ultrafiltrates of human cancer patients. Lymphokine Res 9:225–229PubMedGoogle Scholar
  32. 32.
    Gatanaga T, Hwang C, Kohr W, Cappuccini F, Lucci JA III, Jeffes EWB, Lentz R, Tomich J, Yamamoto RS, Granger GA (1990) Purification and characterization 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 87:8781–8784PubMedGoogle Scholar
  33. 33.
    Loetscher H, Pan Y-CE, Lahm H-W, Gentz R, Brockhaus M, Tabuchi H, Lesslauer W (1990) Molecular cloning and expression of the human 55 kd tumor necrosis factor receptor. Cell 61:351–359PubMedGoogle Scholar
  34. 34.
    Smith CA, Davis T, Anderson D, Solam L, Beckmann MP, Jerzy R, Dower SK, Cosman D, Goodwin RG (1990) A receptor for tumor necrosis factor defines an unusual family of cellular and viral proteins. Science 248:1019–1023PubMedGoogle Scholar
  35. 35.
    Loetscher H, Gentz R, Zulauf M, Lustig A, Tabuchi H, Schlaeger E-J, Brockhaus M, Gallati H, Manneberg M, Lesslauer W (1991) Recombinant 55-kDa tumor necrosis factor (TNF) receptor. Stoichiometry of binding to TNFα and TNFβ and inhibition of TNF activity. J Biol Chem 266:18324–18329PubMedGoogle Scholar
  36. 36.
    Fiers W, Beyaert R, Brouckaert P, Decoster E, De Valck D, Everaerdt B, Grooten J, Lenaerts A, Libert C, Schulze-Osthoff K, Takahashi N, Tavernier J, Van Bladel S, Van Dorpe C, Vanhaesebroeck B, Van Ostade X, Van Roy F (1992) Tumor necrosis factor: mechanism of action at the molecular, cellular, and in vivo level. In: Osawa T, Bonavida B (eds) Tumor necrosis factor: Structure-function relationship and clinical application. Karger, Basel, pp 66–73Google Scholar
  37. 37.
    Yonehara S, Ishii A, Yonehara M (1989) A cell-killing monoclonal antibody (anti-Fas) to a cell surface antigen co-downregulated with the receptor of tumor necrosis factor. J Exp Med 169:1747–1756PubMedGoogle Scholar
  38. 38.
    Itoh N, Yonehara S, Ishii A, Yonehara M, Mizushima S, Sameshima M, Hase A, Seto Y, Nagata S (1991) The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 66:233–243PubMedGoogle Scholar
  39. 39.
    Engelmann H, Holtmann H, Brakebusch C, Avni YS, Sarov I, Nophar Y, Hadas E, Leitner O, Wallach D (1990) Antibodies to a soluble form of a tumor necrosis factor (TNF) receptor have TNF-like activity. J Biol Chem 265:14497–14504PubMedGoogle Scholar
  40. 40.
    Winzen R, Wallach D, Engelmann H, Nophar Y, Brakebusch C, Kemper O, Resch K, Holtmann H (1992) Selective decrease in cell surface expression and mRNA levels of the 55-kDa tumor necrosis factor receptor during differentiation of HL-60 cells into macrophage-like but not granulocyte-like cells. J Immunol 148:3454–3460PubMedGoogle Scholar
  41. 41.
    Adolf GR, Frühbeis B (1992) Monoclonal antibodies to soluble human TNF receptor (TNF binding protein) enhances its ability to block TNF toxicity. Cytokine 4:180–184PubMedGoogle Scholar
  42. 42.
    Van Ostade X, Tavernier J, Prangé T, Fiers W (1991) Localization of the active site of human tumour necrosis factor (hTNF) by mutational analysis. EMBO J 10:827–836PubMedGoogle Scholar
  43. 43.
    Thoma B, Grell M, Pfizenmaier K, Scheurich P (1990) Identification of a 60-kD tumor necrosis factor (TNF) receptor as the major signal transducing component in TNF receptors. J Exp Med 172:1019–1023PubMedGoogle Scholar
  44. 44.
    Taltaglia L, Weber RF, Figari IS, Reynolds C, Palladino MA, Goeddel DV (1991) The two different receptors for tumor necrosis factor mediate distinct cellular responses. Proc Natl Acad Sci USA 88:9292–9296PubMedGoogle Scholar
  45. 45.
    Hohmann H-P, Brockhaus M, Baeuerle PA, Remy R, Kolbeck R, van Loon APGM (1990) Expression of the type A and B tumor necrosis factor (TNF) receptors is independently regulated, and both receptors mediate activation of the transcription factor NF-KB. J Biol Chem 265:22409–22417PubMedGoogle Scholar
  46. 46.
    Heller RA, Song K, Fan N, Chang DJ (1992) The p70 tumor necrosis factor receptor mediates cytotoxicity. Cell 70:47–56PubMedGoogle Scholar
  47. 47.
    Abe Y, Gatanaga M, Osuka Y, Kimura S, Granger GA, Gatanaga T (1993) Role of 55- and 75-kDa TNF membrane receptors in the regulation of ICAM-1 expression by HL-60 human promyelocytic leukemia cells in vitro. J Immunol 150: 5070–5079PubMedGoogle Scholar
  48. 48.
    Aderka D, Engelmann H, Hornik V, Skornick Y, Levo Y, Wallach D, Kushtai G (1991) Increased serum levels of soluble receptors for tumor necrosis factor in cancer patients. Cancer Res 51:5602–5607PubMedGoogle Scholar
  49. 49.
    Grosen E, Yamamoto RS, Ioli G, Gatanaga T, Ininns E, DiSaia P, Granger GA (1991) Primary tumor cultures from patients with gynecologic malignancies release TNF/LT blocking factors in vitro. In: Abstracts: Third International Workshop on Cytokines, pp 501Google Scholar
  50. 50.
    Digel W, Porzsolt F, Schmid M, Herrmann F, Lesslauer W, Brockhaus M (1992) High levels of circulating soluble receptors for tumor necrosis factor in Hairy cell leukemia and type B chronic lymphocytic leukemia. J Clin Invest 89:1690–1693PubMedGoogle Scholar
  51. 51.
    Waage A, Liabakk N, Lamvik J, Espevik T (1991) Expression of p55 and p75 TNF receptors on neoplastic cells from patients with chronic lymphocytic leukemia. In: Abstracts: Third International Workshop on Cytokines, pp 479Google Scholar
  52. 52.
    Aderka D, Engelmann H, Wysenbeek AJ, Levo Y (1992) The possible role of tumor necrosis factor (TNF) and its natural inhibitors, the soluble-TNF receptors, in autoimmune diseases. Isr J Med Sci 28:126–130PubMedGoogle Scholar
  53. 53.
    Adolf GR, Apfler I (1991) A monoclonal antibody-based immunoassay for quantitation of human tumor necrosis factor binding protein I, a soluble fragment of the 60 kDa TNF receptor, in biological fluids. J Immunol Methods 143:127–136PubMedGoogle Scholar
  54. 54.
    Spinas GA, Keller U, Brockhaus M (1992) Release of soluble receptors for tumor necrosis factor (TNF) in relation to circulating TNF during experimental endotoxinemia. J Clin Invest 90:533–536PubMedGoogle Scholar
  55. 55.
    Girardin E, Roux-Lombard P, Grau GE, Suter P, Gallati H, the J5 study group, Dayer J-M (1992) Imbalance between tumour necrosis factor-alpha and soluble TNF receptor concentrations in severe meningococcaemia. Immunology 76:20–23PubMedGoogle Scholar
  56. 56.
    Ryffel B, Brockhaus M, Greiner B, Mihatsch MJ, Gudat F (1991) Tumor necrosis factor receptor distribution in human lymphoid tissue. Immunology 74:446–452PubMedGoogle Scholar
  57. 57.
    Erikstein BK, Smeland EB, Bolmhoff HK, Funderud S, Prydz K, Lesslauer W, Espevik T (1991) Independent regulation of 55-kDa and 75-kDa tumor necrosis factor receptors during activation of human peripheral blood B lymphocytes. Eur J Immunol 21:1033–1037PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1994

Authors and Affiliations

  • Yasuhito Abe
    • 1
  • Yuji Watanabe
    • 1
  • Shigeru Kimura
    • 1
  1. 1.The Second Department of SurgeryEhime University School of MedicineJapan

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