Skip to main content
SpringerLink
Log in

The Biology of Cachectin/Tumor Necrosis Factor

  • Chapter
Growth Factors, Differentiation Factors, and Cytokines

Abstract

The immune system produces cytokines and other humoral factors to protect the host when threatened by inflammatory agents, microbial invasion, or injury. In some cases this complex defense network successfully restores normal homeostasis, but at other times the overproduction of participating immunoregulatory mediators may be deleterious. Some examples of immune system-mediated injury have been extensively investigated including anaphylactic shock, autoimmune disease, and immune complex disorders. More recently it has become clear that the cytokine cachectin/tumor necrosis factor (TNF) occupies a key role in the pathological physiology associated with diverse inflammatory states and other serious illnesses including septic shock and cachexia. For example, when cachectin/TNF is produced by resident macrophages during early microbial infection it mediates an inflammatory response that may alienate and repel the attacking organisms. If the infection spreads, however, the subsequent release of large quantities of cachectin/TNF into the circulation is catastrophic and triggers a state of lethal shock. These toxic effects occur by direct effects on host cells and by interactions with a cascade of other endogenous mediators including interleukin-1 and interferon-γ. Here we briefly review the history and biology of cachectin/TNF, and discuss the potential for modulating the effects of this pluripotent molecule in a variety of pathologic states.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Bakouche O, Ichinose Y, Heicapell R, Fidler IJ, Lachman LB (1988) Plasma membrane-associated tumor necrosis factor: a non-integral membrane protein possibly bound to its own receptor. J Immunol 140:1142–1147

    PubMed  CAS  Google Scholar 

  • Balkwill F, Osborne R, Burke F, Naylor S, Talbot D, Durbin H, Tavernier J, Fiers W (1987) Evidence for tumour necrosis factor/cachectin production in cancer. Lancet 2:1229–1232

    Article  PubMed  CAS  Google Scholar 

  • Beutler B, Milsark IW, Cerami AC (1985a) Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science 229:869–871

    Article  PubMed  CAS  Google Scholar 

  • Beutler B, Mahoney J, Le Trang N, Pekala P, Cerami A (1985b) Purification of cachectin, a lipoprotein lipase-suppressing hormone secreted by endotoxin-induced RAW 264.7 cells. J Exp Med 161:984–995

    Article  PubMed  CAS  Google Scholar 

  • Beutler B, Greenwald D, Hulmes JD, Chang M, Pan YC, Mathison J, Ulevitch R, Cerami A (1985c) Identity of tumour necrosis factor and the macrophage-secreted factor cachectin. Nature 316:552–554

    Article  PubMed  CAS  Google Scholar 

  • Beutler B, Tkacenko V, Milsark I, Krochin N, Cerami A (1986a) Effect of gamma interferon on cachectin expression by mononuclear phagocytes. Reversal of the lps (endotoxin resistance) phenotype. J Exp Med 164:1791–1796

    Article  PubMed  CAS  Google Scholar 

  • Beutler B, Krochin N, Milsark IW, Luedke C, Cerami A (1986b) Control of cachectin (tumor necrosis factor) synthesis: mechanism of endotoxin resistance. Science 232:977–980

    Article  PubMed  CAS  Google Scholar 

  • Beutler BA, Milsark IW, Cerami A (1985d) Cachectin/tumor necrosis factor: production, distribution, and metabolic fate in vivo. J Immunol 135:3972–3977

    PubMed  CAS  Google Scholar 

  • Blick M, Sherwin SA, Rosenblum M, Gutterman J (1987) Phase I study of recombinant tumor necrosis factor in cancer patients. Cancer Res 47:2986–2989

    PubMed  CAS  Google Scholar 

  • Brownlee M, Cerami A, Vlassara H (1988) Advanced glycosylation end products in tissue and the biochemical basis of diabetic complications. N Engl J Med 318:1315–1321

    Article  PubMed  CAS  Google Scholar 

  • 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 166:1390–1404

    Article  PubMed  CAS  Google Scholar 

  • Caput D, Beutler B, Hartog K, Thayer R, Brown Shimer S, Cerami A (1986) Identification of a common nucleotide sequence in the 3’-untranslated region of mRNA molecules specifying inflammatory mediators. Proc Natl Acad Sci USA 83:1670–1674

    Article  PubMed  CAS  Google Scholar 

  • 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 72:3666–3670

    Article  PubMed  CAS  Google Scholar 

  • 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 162:2163–2168

    Article  PubMed  CAS  Google Scholar 

  • Dinarello CA, Cannon JG, Wolff SM, Bemheim HA, Beutler B, Cerami A, Figari IS, Palladino MA Jr, OConnor JV (1986) Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1. J Exp Med 163 :1433–1450

    Article  PubMed  CAS  Google Scholar 

  • Djeu JY, Blanchard DK, Richards AL, Friedman H (1988) Tumor necrosis factor induction by Candida albicans from human natural killer cells and monocytes. J Immunol 141:4047–4052

    PubMed  CAS  Google Scholar 

  • Feingold KR, Grunfeld C (1987) Tumor necrosis factor-alpha stimulates hepatic lipogenesis in the rat in vivo. J Clin Invest 80:184–190

    Article  PubMed  CAS  Google Scholar 

  • Fraker DL, Stovroff MC, Merino MJ, Norton JA (1988) Tolerance to tumor necrosis factor in rats and the relationship to endotoxin tolerance and toxicity. J Exp Med 168:95–105

    Article  PubMed  CAS  Google Scholar 

  • Girardin E, Grau GE, Dayer J-M, Roux-Lombard P, The JS Study Group, Lambert P-H (1988) Tumor necrosis factor and interleukin-1 in the serum of children with severe infectious purpura. N Engl J Med 319:397–400

    Article  PubMed  CAS  Google Scholar 

  • Hesse DG, Tracey KJ, Fong Y, Manogue KR, Palladino MA Jr, Cerami A, Shires GT, Lowry SF (1988) Cytokine appearance in human endotoxemia and primate bacteremia. Surg Gynecol Obstet 166:147–153

    PubMed  CAS  Google Scholar 

  • Kawakami M, Cerami A (1981) Studies of endotoxin-induced decrease in lipoprotein lipase activity. J Exp Med 154:631–639

    Article  PubMed  CAS  Google Scholar 

  • Kettelhut IC, Fiers W, Goldberg AL (1987) The toxic effects of tumor necrosis factor in vivo and their prevention by cyclooxygenase inhibitors. Proc Natl Acad Sci USA 84:4273–4277

    Article  PubMed  CAS  Google Scholar 

  • 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 53:45–53

    Article  PubMed  CAS  Google Scholar 

  • Lahdevirta J, Maury CPJ, Teppo A-M, Repo H (1988) Elevated levels of circulating cachectin/ tumor necrosis factor in patients with acquired immunodeficiency syndrome. Am J Med 85:289–291

    Article  PubMed  CAS  Google Scholar 

  • Lee MD, Zentella A, Pekala PH, Cerami A (1987) Effect of endotoxin-induced monokines on glucose metabolism in the muscle cell line L6. Proc Natl Acad Sci USA 84:2590–2594

    Article  PubMed  CAS  Google Scholar 

  • Leibovich SJ, Polverini PJ, Shepard HM, Wiseman DM, Shively V, Nuseir N (1987) Macrophage-induced angiogenesis is mediated by tumour necrosis factor-alpha. Nature 329:630–632

    Article  PubMed  CAS  Google Scholar 

  • Mathison JC, Wolfson E, Ulevitch RJ (1988) Participation of tumor necrosis factor in the mediation of gram-negative bacterial lipopolysaccharide-induced injury in rabbits. J Clin Invest 81:1925–1937

    Article  PubMed  CAS  Google Scholar 

  • Natanson C, Eichenholz PW, Danner RL, Eichhacker PQ, Hoffman WD, Kuo GC, Banks SM, MacVittie TJ, Parrillo JE (1989) Endotoxin and tumor necrosis factor challenge in dogs simulate the cardiovascular profile of human septic shock. J Exp Med 169:823–832

    Article  PubMed  CAS  Google Scholar 

  • Nathan CF (1987a) Neutrophil activation on biological surfaces: Massive secretion of hydrogen peroxide in response to products of macrophages and lymphocytes. J Clin Invest 80:1550–1560

    Article  PubMed  CAS  Google Scholar 

  • Nathan CF (1987b) Secretory products of macrophages. J Clin Invest 79:319–326

    Article  PubMed  CAS  Google Scholar 

  • Nawroth P, Handley D, Matsueda G, DeWaal R, Gerlach H, Blohm D, Stem D (1988) Tumor necrosis factor/cachectin-induced intravascular fibrin formation in meth A fibrosarcomas. J Exp Med 168:637–647

    Article  PubMed  CAS  Google Scholar 

  • Nawroth PP, Stem DM (1986) Modulation of endothelial cell hemostatic properties by tumor necrosis factor. J Exp Med 163:740–745

    Article  PubMed  CAS  Google Scholar 

  • North RJ, Havell EA (1988) The antitumor function of tumor necrosis factor (TNF): II. Analysis of the role of endogenous TNF in endotoxin-induced hemorrhagic necrosis and regression of an established sarcoma. J Exp Med 167:1086–1099

    Article  PubMed  CAS  Google Scholar 

  • Oliff A, Defeo Jones D, Boyer M, Martinez D, Kiefer D, Vuocolo G, Wolfe A, Socher SH (1987) Tumors secreting human TNF/cachectin induce cachexia in mice. Cell 50:555–563

    Article  PubMed  CAS  Google Scholar 

  • Pennica D, Nedwin GE, Hayflick JS, Seeburg PH, Derynck R, Palladino MA Jr, Kohr WJ, Aggarwal BB, Goeddal DV (1984) Human tumor necrosis factor: precursor structure, expression, and homology to lymphotoxin. Nature 312:724–729

    Article  PubMed  CAS  Google Scholar 

  • Pennica D, Hayflick JS, Bringham TS, Palladino MA Jr, Goeddal DV (1985) Cloning and expression in E. coli of the cDNA for murine tumor necrosis factor. Proc Natl Acad Sci USA 82:6060–6064

    Article  PubMed  CAS  Google Scholar 

  • Perlmutter DH, Dinarello CA, Punsal PI, Colten HR (1986) Cachectin/tumor necrosis factor regulates hepatic acute-phase gene expression. J Clin Invest 78:1349–1354

    Article  PubMed  CAS  Google Scholar 

  • Pober JS (1987) Effects of tumor necrosis factor and related cytokines on vascular endothelial cells. Ciba Found Symp 131:88–108

    Google Scholar 

  • Ranges GE, Zlotnik A, Espevik T, Dinarello CA, Cerami A, Palladino MA Jr (1988) Tumor necrosis factor-alpha/cachectin is a growth factor for thymocytes. Synergistic interactions with other cytokines. J Exp Med 167:1472–1478

    Article  PubMed  CAS  Google Scholar 

  • Rouzer CA, Cerami A (1980) Hypertriglyceridemia associated with Trypanosoma brucei infections in rabbits: role of effective triglyceride removal. Mol Biochem Parasitol 2:31–38

    Article  PubMed  CAS  Google Scholar 

  • Scuderi P, Sterling KE, Lam KS, Finley PR, Ryan KJ, Ray CG, Petersen E, Slymen DJ, Salmon SE (1986) Raised serum levels of tumour necrosis factor in parasitic infections. Lancet 2:1364–1365

    Article  PubMed  CAS  Google Scholar 

  • Smith RA, Baglioni C (1987) The active form of tumor necrosis factor is a trimer. J Biol Chem 262:6951

    PubMed  CAS  Google Scholar 

  • Socher SH, Martinez DM, Craig JB, Kuhn JG, Oliff A (1988) Tumor necrosis factor not detectable in patients with clinical cancer cachexia. JNCI 80:595–598

    PubMed  CAS  Google Scholar 

  • Spriggs DR, Sherman ML, Frei E III, Kufe DW (1987) Clinical studies with tumour necrosis factor. Ciba Found Symp 131:206–227

    PubMed  CAS  Google Scholar 

  • Spriggs DR, Sherman ML, Michie HR, Arthur KA, Imamura K, Wilmore DW, Frei E III, Kufe DW (1988) Recombinant human tumor necrosis factor administered as a 24-hour intravenous infusion. A phase I pharmacologic study. JNCI 80:1039–1044

    PubMed  CAS  Google Scholar 

  • Starnes HF Jr, Warren RS, Jeevanandam M, Gabrilove JL, Larchian W, Oettgen HF, Brennan MF (1988) Tumor necrosis factor and the acute metabolic response to tissue injury in man. J Clin Invest 82:1321–1325

    Article  PubMed  CAS  Google Scholar 

  • Stephens KE, Ishizaka A, Wu Z, Larrick JW, Raffin TA (1988a) Granulocyte depletion prevents tumor necrosis factor-mediated acute lung injury in guinea pigs. Am Rev Respir Dis 138:1300–1307

    PubMed  CAS  Google Scholar 

  • Stephens KE, Ishizaka A, Larrick JW, Raffin TA (1988b) Tumor necrosis factor causes increased pulmonary permeability and edema. Am Rev Respir Dis 137:1364–1370

    PubMed  CAS  Google Scholar 

  • Sugarman BJ, Aggarwal BB, Hass PE, Figari IS, Palladino MA Jr, Shepard HM (1985) Recombinant human tumor necrosis factor-alpha: Effects on proliferation of normal and transformed cells in vitro. Science 230:943–945

    Article  PubMed  CAS  Google Scholar 

  • Torti FM, Dieckmann B, Beutler B, Cerami A, Ringold GM (1985) A macrophage factor inhibits adipocyte gene expression: an in vitro model of cachexia. Science 229:867–869

    Article  PubMed  CAS  Google Scholar 

  • Tracey KJ, Beugler B, Lowry SF, Merryweather J, Wolpe S, Milsark IW, Hariri RJ, Fahey TJ III, Zentella A, Albert JD, Shires GT, Cerami A (1986) Shock and tissue injury induced by recombinant human cachectin. Science 234:470–474

    Article  PubMed  CAS  Google Scholar 

  • Tracey KJ, Fong Y, Hesse DG, Manogue KR, Lee AT, Kuo GC, Lowry SF, Cerami A (1987a) Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 330:662–664

    Article  PubMed  CAS  Google Scholar 

  • Tracey KJ, Lowry SF, Fahey TJ III, Albert JD, Fong Y, Hesse D, Beutler B, Manogue KR, Calvano S, Wei H, Cerami A, Shires GT (1987b) Cachectin/tumor necrosis factor induces lethal shock and stress hormone responses in the dog. Surg Gynecol Obstet 164:415–422

    PubMed  CAS  Google Scholar 

  • Tracey KJ, Wei H, Manogue KR, Fong Y, Hesse DG, Nguyen HT, Kuo GC, Beutler B, Cotran RS, Cerami A, Lowry SF (1988) Cachectin/tumor necrosis factor induces cachexia, anemia, and inflammation. J Exp Med 167:1211–1227

    Article  PubMed  CAS  Google Scholar 

  • Tsunawaki S, Sporn M, Ding A, Nathan CF (1988) Deactivation of macrophages by transforming growth factor-beta. Nature 334:260–262

    Article  PubMed  CAS  Google Scholar 

  • Vlassara H, Brownlee M, Manogue KR, Dinarello CA, Pasagian A (1988a) Cachectin/TNF and IL-1 induced by glucose-modified proteins: role in normal tissue remodeling. Science 240:1546–1548

    Article  PubMed  CAS  Google Scholar 

  • Vlassara H, Brownlee M, Cerami A (1988b) Specific macrophage receptor activity for advanced glycosylation end products inversely correlates with insulin levels in vivo. Diabetes 37:456–461

    Article  PubMed  CAS  Google Scholar 

  • Waage A, Espevik T (1988) Interleukin 1 potentiates the lethal effect of tumor necrosis factor- alpha/cachectin in mice. J Exp Med 167 :1987–1992

    Article  PubMed  CAS  Google Scholar 

  • Waage A, Halstensen A, Espevik T (1987) Association between tumour necrosis factor in serum and fatal outcome in patients with meningococcal disease. Lancet 1:355–357

    Article  PubMed  CAS  Google Scholar 

  • Warren RS, Starnes HF Jr, Gabrilove JL, Oettgen HF, Brennan MF (1987) The acute metabolic effects of tumor necrosis factor administration in humans. Arch Surg 122:1396–1400

    Article  PubMed  CAS  Google Scholar 

Download references

Authors
  1. K. J. Tracey
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Cerami
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Internal Medicine Division of Endocrinology and Metabolism, University of Heidelberg, Bergheimer Straße 58, D-6900, Heidelberg, Germany

    Andreas Habenicht

Rights and permissions

Reprints and permissions

Copyright information

© 1990 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Tracey, K.J., Cerami, A. (1990). The Biology of Cachectin/Tumor Necrosis Factor. In: Habenicht, A. (eds) Growth Factors, Differentiation Factors, and Cytokines. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-74856-1_26

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-74856-1_26

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-74858-5

  • Online ISBN: 978-3-642-74856-1

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation