Tumour Necrosis Factor and Interleukin-6: Structure and Mechanism of Action of the Molecular, Cellular and in Vivo Level

  • W. Fiers
  • R. Beyaert
  • P. Brouckaert
  • B. Everaerdt
  • J. Grooten
  • G. Haegeman
  • C. Libert
  • P. Suffys
  • N. Takahashi
  • J. Tavernier
  • S. Van Bladel
  • B. Vanhaesebroeck
  • X. Van Ostade
  • F. Van Roy
Part of the NATO ASI Series book series (volume 34)

Abstract

Tumour necrosis factor (TNF) can be induced in experimental animals by injection of Bacillus Calmette-Guérin followed, after one or two weeks, by treatment with lipopolysaccharide (LPS); serum taken a few hours later contains a high concentration of TNF (Carswell et al., 1975). Isolated macrophages, e.g. obtained from placenta, can be activated with interferon-γ (LFN-γ) and 24 h later induced to produce TNF by treatment with LPS. Also monocytic cell lines, such as the human U-937 line or the murine PU-518 line, can be induced under proper conditions to produce TNF (Männel et al., 1980; Fransen et al., 1985; Marmenout et al., 1985). We have cloned and expressed to a high specific activity in E. coli both the human TNF (hTNF) gene (Marmenout et al., 1985) and the murine TNF (mTNF) gene (Fransen et al., 1985). Also the sequence of the rabbit TNF gene has been reported (Ito et al., 1986). TNF obtained from various species is highly homologous (about 80%). The subunit of the mature hTNF is a 157 amino acids long polypeptide (156 amino acids for mTNF). The native protein is a nearly spherical, trimeric molecule, containing 45% β-structure and little or no α-helix (Wingfield et al., 1987). TNF, as its name implies, was originally recognized as a substance causing necrosis of tumours in experimental animals; this was usually demonstrated by means of a methyl-cholanthrene-induced sarcoma, and it may be noted that obtaining effective tumour regression requires a rather strict adherence to a defined treatment protocol. Remarkably (and almost by coincidence as it later turned out), TNF is also selectively toxic to some transformed cell lines. But in the presence of concomitant treatment with interferon (IFN), many more transformed and malignant cell lines become sensitive to the cytotoxic action of TNF (Williamson et al., 1983; Fransen et al., 1986b).

Keywords

Bacillus Sarcoma Interferon Prostaglandin Glucocorticoid 

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References

  1. Bachwich PR, Chensue SW, Larrick JW, Kunke SL (1986) Tumor necrosis factor stimulates interleukin-1 and prostaglandin E2 production in resting macrophages. Biochem Biophys Res Commun 136: 94–101PubMedCrossRefGoogle Scholar
  2. Balkwill FR, Lee A, Aldam G, Moodie E, Thomas JA, Tavernier J, Fiers W (1986) Human tumor xenografts treated with recombinant human tumor necrosis factor alone or in combination with interferons. Cancer Res 46: 3990–3993PubMedGoogle Scholar
  3. Balkwill FR, Ward BG, Moodie E, Fiers W (1987) Therapeutic potential of tumor necrosis factor-α and γ-interferon in experimental human ovarian cancer. Cancer Res 47: 4755–4758PubMedGoogle Scholar
  4. Bevilacqua MP, Pober JS, Majeau GR, Fiers W, Cotran RS, Gimbrone MA (1986) Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: characterization and comparison with the actions of interleukin-1. Proc Natl Acad Sci USA 83: 4533–4537PubMedCrossRefGoogle Scholar
  5. Bevilacqua MP, Wheeler ME, Pober JS, Fiers W, Mendrick DL, Cotran RS, Gimbrone MA (1987) Endothelial-dependent mechanisms of leukocyte adhesion: regulation by interleukin 1 and tumor necrosis factor. In: Movat HZ (ed) Leukocyte emigration and its sequelae. Karger, Basel, p 79Google Scholar
  6. Brouckaert PGG, Leroux-Roels GG, Guisez Y, Tavernier J, Fiers W (1986) In vivo antitumor activity of recombinant human and murine TNF, alone and in combination with murine IFN-γ, on a syngeneic murine melanoma. Int J Cancer 38: 763–769PubMedCrossRefGoogle Scholar
  7. Brouckaert PG, Everaerdt B, Libert C, Takahashi N, Fiers W (1989) Species specificity and involvement of other cytokines in endotoxic shock action of recombinant tumour necrosis factor in mice. Ag Act (in press)Google Scholar
  8. Brouckaert P, Spriggs DR, Demetri G, Kufe DW, Fiers W (submitted) Circulating interleukin-6 during a continuous infusion of tumour necrosis factor and interferon-γGoogle Scholar
  9. Broudy VC, Kaushansky K, Segal GM, Harlan JM, Adamson JW (1986) Tumor necrosis factor type alpha stimulates human endothelial cells to produce granulocyte/macrophage colony stimulating factor. Proc Natl Acad Sci USA 83: 7467–7471PubMedCrossRefGoogle Scholar
  10. Bussolino F, Camussi G, Baglioni C (1988) Synthesis and release of platelet-activating factor by human vascular endothelial cells treated with tumor necrosis factor or interleukin 1α. J Biol Chem 263: 11856–11861PubMedGoogle Scholar
  11. Camussi G, Bussolino F, Salvidio G, Baglioni C (1987) Tumor necrosis factor/cachectin stimulates peritoneal macrophages, polymorphonuclear neutrophils, and vascular endothelial cells to synthesize and release platelet-activating factor. J Exp Med 166: 1390–1404PubMedCrossRefGoogle Scholar
  12. Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B (1975) An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci USA 72: 3666–3670PubMedCrossRefGoogle Scholar
  13. Collins T, Lapierre LA, Fiers W, Strominger 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: 446–450PubMedCrossRefGoogle Scholar
  14. Content J, De Wit L, Pierard D, Derynck R, De Clercq E, Fiers W (1982) Secretory proteins induced in human fibroblasts under conditions used for the production of interferon p. Proc Natl Acad Sci USA 79: 2768–2772PubMedCrossRefGoogle Scholar
  15. Coulie PG, Cayphas S, Vink A, Uyttenhove C, Van Snick J (1987) Interleukin-HP1- related hybridoma and plasmacytoma growth factors induced by lipopolysaccharide in vivo. Eur J Immunol 17: 1217–1220PubMedCrossRefGoogle Scholar
  16. Dayer JM, Beutler B, Cerami A (1985) Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E2 production by human synovial cells and dermal fibroblasts. J Exp Med 162: 2163–2168PubMedCrossRefGoogle Scholar
  17. Defilippi P, Poupart P, Tavernier J, Fiers W, Content J (1987) Induction and regulation of mRNA encoding 26-kDa protein in human cell lines treated with recombinant human tumor necrosis factor. Proc Natl Acad Sci USA 84: 4557–4561PubMedCrossRefGoogle Scholar
  18. Dinarello CA, Cannon JG, Wolff SM, Bernheim HA, Beutler B, Cerami A, Figari IS, Palladino A Jr, O’Connor JV (1986) Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1. J Exp Med 163: 1433–1450PubMedCrossRefGoogle Scholar
  19. Fiers W, Brouckaert P, Devos R, Fransen L, Leroux-Roels G, Remaut E, Suffys P, Tavernier J, Van der Heyden J, Van Roy F (1986a) Lymphokines and monokines in anti-cancer therapy. Cold Spring Harbor Symp Quant Biol 51: 587–595PubMedGoogle Scholar
  20. Fiers W, Brouckaert P, Guisez Y, Remaut E, Van Roy F, Devos R, Fransen L, Leroux-Roels G, Marmenout A, Tavernier J, Van der Heyden J (1986b) Recombinant interferon gamma and its synergism with tumor necrosis factor in the human and mouse systems. In: Stewart II WE, Schellekens H (eds) The biology of the interferon system 1985. Elsevier Science Publishers, Amsterdam, p 241Google Scholar
  21. Fiers W, Brouckaert P, Goldberg AL, Kettelhut I, Suffys P, Tavernier J, Vanhaesebroeck B, Van Roy F (1987) Structure function relationship of tumour necrosis factor and its mechanism of action. In: Ciba Foundation Symposium 131, Tumour necrosis factor and related cytotoxins. John Wiley & Sons, Chichester, p 109Google Scholar
  22. Fiers W, Brouckaert P, Content J, Contreras R, Everaerdt B, Guisez Y, Libert C, Spriggs D, Takahashi N, Tison B, Vandenabeele P, Van Snick J (in press) Interleukin-6: biological function and regulation of the gene expression in vitro and in vivo. Adv. Immunopharmacol 4Google Scholar
  23. Fransen L, Müller R, Marmenout A, Tavernier J, Van der Heyden J, Kawashima E, Chollet A, Tizard R, Van Heuverswyn H, Van Vliet A, Ruysschaert MR, Fiers W (1985) Molecular cloning of mouse tumour necrosis factor cDNA and its eukaryotic expression. Nucl Acids Res 13: 4417–4429PubMedCrossRefGoogle Scholar
  24. Fransen L, Ruysschaert MR, Van der Heyden J, Fiers W (1986a) Recombinant tumour necrosis factor: species specificity for a variety of human and murine transformed cell lines. Cell Immunol 100: 260–267PubMedCrossRefGoogle Scholar
  25. Fransen L, Van der Heyden J, Ruysschaert R, Fiers W (1986b) Recombinant tumor necrosis factor: its effect and its synergism with interferon-γ on a variety of normal and transformed human cell lines. Eur J Cancer Clin Oncol 22: 419–426PubMedCrossRefGoogle Scholar
  26. Galanos C, Freudenberg MA, Reutter W (1979) Galactosamine induced sensitization to the lethal effects of endotoxin. Proc Natl Acad Sci USA 76: 5939–5943PubMedCrossRefGoogle Scholar
  27. Gamble JR, Harlan JM, Klebanoff SJ, Vadas MA (1985) Stimulation of the adherence of neutrophils to umbilical vein endothelium by human recombinant tumor necrosis factor. Proc Natl Acad Sci USA 82: 8667–8671PubMedCrossRefGoogle Scholar
  28. Gresser I, Belardelli F, Tavernier J, Fiers W, Podo F, Federico M, Carpinelli G, Duvillard P, Prade M, Maury C, Bandu MT, Maunory MT (1986) Antitumor effects of interferon in mice injected with interferon-sensitive and interferon-resistant Friend leukemia cells. V. Comparisons with tumor necrosis factor. Int J Cancer 38: 771–778Google Scholar
  29. Haegeman G, Content J, Volckaert G, Derynck R, Tavernier J, Fiers W (1986) Structural analysis of the sequence coding for an inducible 26-kDa protein in human fibroblasts. Eur J Biochem 159: 625–632PubMedCrossRefGoogle Scholar
  30. Hepburn A, Boeynaems JM, Fiers W, Dumont JE (1987) Modulation of tumor necrosis factor-α cytotoxicity in L929 cells by bacterial toxins, hydrocortisone and inhibitors of arachidonic acid metabolism. Biochem Biophys Res Commun 149: 815–822PubMedCrossRefGoogle Scholar
  31. Hirano T, Matsuda T, Hosoi K, Okano A, Matsui H, Kishimoto T (1988) Absence of antiviral activity in recombinant B cell stimulatory factor 2 (BSF-2). Immunol Lett 17: 41–45PubMedCrossRefGoogle Scholar
  32. Ito H, Yamamoto S, Kuroda S, Sakamoto H, Kajihara J, Kiyota T, Hayashi H, Kato M, Seko M (1986) Molecular cloning and expression in E. coli of the cDNA coding for rabbit tumor necrosis factor. DNA 5: 149–156Google Scholar
  33. Kettelhut I, Fiers W, Goldberg A (1987) The toxic effects of tumor necrosis factor in vivo and their prevention by cyclooxygenase inhibitors. Proc Nad Acad Sci USA 84: 4273–4277CrossRefGoogle Scholar
  34. Kurt-Jones EA, Fiers W, Pober JS (1987) Membrane interleukin 1 induction on human endothelial cells and dermal fibroblasts. J Immunol 139: 2317–2324PubMedGoogle Scholar
  35. Lehmann V, Freudenberg MA, Galanos C (1987) Lethal toxicity of lipopolysaccharide and tumor necrosis factor in normal and D-galactosamine-treated mice. J Exp Med 165: 657–663PubMedCrossRefGoogle Scholar
  36. Libby P, Ordovas JM, Auger KR, Robbins AH, Birinyi LK, Dinarello CA (1986) Endotoxin and tumor necrosis factor induce interleukin-1 gene expression in adult human vascular endothelial cells. Am J Pathol 124: 179–185PubMedGoogle Scholar
  37. Männel DN, Moore RN, Mergenhagen SE (1980) Macrophages as a source of tumoricidal activity (tumor-necrotizing factor). Infect Immun 30: 523–530PubMedGoogle Scholar
  38. Mareel M, Dragonetti C, Tavernier J, Fiers W (1988) Tumor selective cytotoxic effects of murine tumor necrosis factor (TNF) and interferon-gamma (IFN-gamma) in organ culture of B16 melanoma cells and heart tissue. Int J Cancer 42: 470–473PubMedCrossRefGoogle Scholar
  39. Marmenout A, Fransen L, Tavernier J, Van der Heyden J, Tizard R, Kawashima E, Shaw A, Johnson MJ, Semon D, Müller R, Ruysschaert MR, Van Vliet A, Fiers W (1985) Molecular cloning and expression of human tumor necrosis factor and comparison with mouse tumor necrosis factor. Eur J Biochem 152: 515–522PubMedCrossRefGoogle Scholar
  40. Marquet RL, IJzermans JNM, De Bruin RWF, Fiers W, Jeekel J (1987) Anti-tumor activity of recombinant mouse tumor necrosis factor ( TNF) on colon cancer in rats is promoted by recombinant rat interferon gamma; toxicity is reduced by indomethacin. Int J Cancer 40: 550–553Google Scholar
  41. Messadi DV, Pober JS, Fiers W, Gimbrone MA, Murphy GF (1987) Induction of an activation antigen on postcapillary venular endothelium in human skin organ culture. J Immunol 139: 1557–1562PubMedGoogle Scholar
  42. Mosselmans R, Hepburn A, Dumont JE, Fiers W, Galand P (1988) Endocytic pathway of recombinant murine tumor necrosis factor in L-929 cells. J Immunol (in press)Google Scholar
  43. Munker R, Gasson J, Ogawa M, Koeffler HP (1986) Recombinant human TNF induces production of granulocyte-monocyte colony-stimulating factor. Nature 323: 79–82PubMedCrossRefGoogle Scholar
  44. Nawroth PP, Bank I, Handley D, Cassimeris J, Chess L, Stern D (1986a) Tumor necrosis factor/cachectin interacts with endothelial cell receptors to induce release of interleukin Exp Med 163: 1363–1375Google Scholar
  45. Nawroth PP, Stern DM (1986b) Modulation of endothelial cell homostatic properties by tumor necrosis factor. J Exp Med 163: 740–745PubMedCrossRefGoogle Scholar
  46. Parant F, Fiers W, Parant M (submitted) Absence of species preference of human and murine tumor necrosis factor in toxicity and anti-infectious studies in mice.Google Scholar
  47. Pober JS, Bevilacqua MP, Mendrick DL, Lapierre LA, Fiers W, Gimbrone MA (1986) Two distinct monokines, interleukin 1 and tumor necrosis factor, each independently induce biosynthesis and transient expression of the same antigen on the surface of cultured human vascular endothelial cells. J Immunol 136: 1680–1687PubMedGoogle Scholar
  48. Pober JS, Lapierre LA, Stolpen AH, Brock TA, Springer TA, Fiers W, Bevilacqua TA, Mendrick DL, Gimbrone MA (1987) Activation of cultured human endothelial cells by recombinant lymphotoxin: comparison with tumor necrosis factor and interleukin 1 species. J. Immunol 138: 3319–3324PubMedGoogle Scholar
  49. Poupart P, Vandenabeele P, Cayphas S, Van Snick J, Haegeman G, Kruys V, Fiers W, Content J (1987) B-cell growth modulating and differentiating activity of recombinant human 26 kDa protein (BSF-2, HuIFN-β2, HPGF ). EMBO J 6: 1219–1224Google Scholar
  50. Reis LFL, Le J, Hirano T, Kishimoto T, Vilcek J (1988) Antiviral action of tumor necrosis factor in human fibroblasts is not mediated by B cell stimulatory factor 2/IFN-β 2, and is inhibited by specific antibodies to IFN-β. J Immunol 140: 1566–1570PubMedGoogle Scholar
  51. Stolpen AH, Guinan EC, Fiers W, Pober JS (1986) Recombinant tumor necrosis factor and immune interferon act singly and in combination to reorganize human vascular endothelial cell monolayers. Am J Pathol 123: 16–24PubMedGoogle Scholar
  52. Suffys P, Beyaert R, Van Roy F, Fiers W (1987) Reduced tumour necrosis factor-induced cytotoxicity by inhibitors of the arachidonic acid metabolism. Biochem Biophys Res Commun 149: 735–743PubMedCrossRefGoogle Scholar
  53. Suffys P, Van Roy F, Fiers W (1988) Tumour necrosis factor and interleukin 1 activate phospholipase in rat chondrocytes. FEBS Lett 232: 24–28PubMedCrossRefGoogle Scholar
  54. Van Hinsbergh VWM, Kooistra T, Princen HMG, Fiers W, Emeis JJ (1988) Tumor necrosis factor increases the production of plasminogen activator inhibitor in human endothelial cells in vitro and in rats in vivo. Blood (in press)Google Scholar
  55. Van Hinsbergh VWM, Van den Berg EA, Fiers W, Dooijewaard G (submitted) Tumor necrosis factor induces the production of urokinase-type plasminogen activator by human endothelial cells.Google Scholar
  56. Van Snick J, Cayphas S, Szikora JP, Renauld JC, Van Roost E, Boon T, Simpson RJ (1988) cDNA cloning of murine interleukin-HP1: homology with human interleukin 6. Eur J Immunol 18: 193–197Google Scholar
  57. Vilcek J, Palombella VJ, Henriksen-DeStefano D, Swenson C, Feinman R, Hirai M, Tsujimoto M (1986) Fibroblast growth enhancing activity of tumor necrosis factor and its relationship to other polypeptide growth factors. J Exp Med 163: 632–643PubMedCrossRefGoogle Scholar
  58. Wallach D, Holtmann H, Engelmann H, Nophar Y (1988) Sensitization and desensitization to lethal effects of tumor necrosis factor and EL-1. J Immunol 140:29– 94–2999Google Scholar
  59. Williamson BD, Carswell EA, Rubin BY, Prendergast JS, Old LJ (1983) Human tumor necrosis factor produced by human B-cell lines: synergistic cytotoxic interaction with human interferon. Proc Natl Acad Sci USA 80: 5397–5401PubMedCrossRefGoogle Scholar
  60. Wingfield P, Pain RH, Craig S (1987) Tumour necrosis factor is a compact trimer. FEBS Lett 211: 179–184PubMedCrossRefGoogle Scholar
  61. Zavoico GB, Ewenstein BM, Schafer AI, Pober JS (submitted) Interleukin-1 and related cytokines enhance thrombin stimulated PGI2 production in cultured endothelial cells without affecting thrombin-stimulated von Willebrand factor secretion or platelet activating factor biosynthesis.Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1989

Authors and Affiliations

  • W. Fiers
    • 1
  • R. Beyaert
    • 1
  • P. Brouckaert
    • 1
  • B. Everaerdt
    • 1
  • J. Grooten
    • 1
  • G. Haegeman
    • 1
  • C. Libert
    • 1
  • P. Suffys
    • 1
  • N. Takahashi
    • 1
  • J. Tavernier
    • 1
  • S. Van Bladel
    • 1
  • B. Vanhaesebroeck
    • 1
  • X. Van Ostade
    • 1
  • F. Van Roy
    • 1
  1. 1.Laboratory of Molecular BiologyState UniversityGentBelgium

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