Skip to main content
SpringerLink
Log in

Endotoxin as an inducer of cytokines

  • Chapter
Cytokines in Severe Sepsis and Septic Shock

Part of the book series: Progress in Inflammation Research ((PIR))

  • 106 Accesses

Abstract

Endotoxins were suspected of being related to the pathophysiology of Gram-negative bacterial infections since the time when R. Pfeiffer and E. Centanni independently found that different species of these microorganisms contained a heat stable pyrogenic material. This was termed endotoxin based on its tight association with the microorganisms. Intensive studies, in particular during the last two decades, have established the detailed chemical structure of the endotoxins in most of the clinically-relevant microbes (reviewed in [1]). The finding that application of highly purified endotoxins to experimental animals and humans induces major signs of bacteriosis, such as fever, hemodynamic disorders, shock, and many others (reviewed in [2]) gave reason to suspect endotoxin as being a major component in the pathogenesis of sepsis. Bacterial components, including endotoxins, have been administered to patients for almost one hundred years as a treatment for malignancies [3] and as an experimental model for the acute inflammatory response with similarities to the initial response of humans to bacterial sepsis.

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 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover 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

  1. Rietschel ETh, Brade H, Holst O, Brade L, Müller-Loennis S, Mamat U, Zähringer U, Beckmann F, Seydel U, Brandenburg K et al (1996) Bacterial endotoxin: chemical constitution, biological recognition, host response, and immunological detoxification. In: ETh Rietschel, H Wagner (eds): Pathology of septic shock, Curr Top Microbiol Immunol, Vol 216. Springer-Verlag, Berlin, 40–81

    Chapter  Google Scholar 

  2. Martich GD, Boujoukos AJ, Suffredini AF (1993) Response of man to endotoxin. Immunobiology 187: 403–416

    Article  PubMed  CAS  Google Scholar 

  3. Nauts HC (1989) Bacteria and cancer — antagonisms and benefits. Cancer Surveys 8: 713–723

    PubMed  CAS  Google Scholar 

  4. Suffredini AF, Fromm RE, Parker MM, Brenner M, Kovacs JA, Wesley RA, Parrillo JE (1989)The cardiovascular response of normal humans to the administration of endotoxin. The New Engl J Medicine 321: 280–287

    Article  CAS  Google Scholar 

  5. van Deventer SJH, Buller HR, ten Cate JW, Aarden LA, Hack CE, Sturk A (1990) Exper-imental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood 76: 2520–2526

    PubMed  Google Scholar 

  6. Suffredini AF, Shelhamer JH, Neumann RD, Brenner M, Baltaro RJ, Parrillo JE (1992) Pulmonary and oxygen transport effects of intravenously administered endotoxin in normal humans. Am Rev Respir Dis 145: 1398–1403

    PubMed  CAS  Google Scholar 

  7. Suffredini AF, Harpel PC, Parrillo JE (1989) Promotion and subsequent inhibition of plasminogen activation after administration of intravenous endotoxin to normal subjects. N Engl J Med 320: 1165–1172

    Article  PubMed  CAS  Google Scholar 

  8. De La Cadena RA, Suffredini AF, Page JD, Pixley RA, Kaufman N, Parrillo JE, Colman RW (1993) Activation of the kallikrein-kinin system after endotoxin administration to normal human volunteers. Blood 81: 3313–3317

    Google Scholar 

  9. Moore FD, Moss NA, Revhaug A, Wilmore D, Mannick JA, Rodrick ML (1987) A single dose of endotoxin activates neutrophils without activating complement. Surgery 102: 200–205

    PubMed  CAS  Google Scholar 

  10. Martich GD, Van Dervort AL, Danner RL, Suffredini AF (1992) Intravenous endotoxin administration to normal humans primes neutrophils for an enhanced respiratory burst. Crit Care Med 20: 100

    Google Scholar 

  11. Smith PD, Suffredini AF, Lamerson CL, Allen JB, McCartney-Frances N, Parvillo JE, Wahl SM (1988) Endotoxin administration to normal humans causes increased alveolar permeability and priming of alveolar macrophages to produce enhanced superoxide and IL-1 production. Clin Res 36: 374A

    Google Scholar 

  12. Foreman NK, Wang WC, Cullen EJ, Stidham GL, Pearson TA, Shenep JL (1991) Endotoxin shock after transfusion of contaminated red blood cells in a child with sickle cell disease. Pediatr Inf Dis J 10: 624–626

    Article  CAS  Google Scholar 

  13. Da Silva AMT, Kaulbach HC, Chuidian FS, Lambert DR, Suffredini AF, Danner RL (1993) Brief report: shock and multiple-organ dysfunction after selfadministration of salmonella endotoxin. N Engl J Med 328: 1457–1460

    Article  Google Scholar 

  14. Levin J, Poore TE, Neil BA, Zauber NP, Oser RS (1970) Detection of endotoxin in the blood of patients with sepsis due to gram-negative bacteria. N Engl J Med 283: 1313–1316

    Article  PubMed  CAS  Google Scholar 

  15. van Deventer SJH, Buller HR, ten Cate JW, Sturk A, Pauw W (1988) Endotoxaemia: an early predictor of septicaemia in febrile patients. Lancet 605–608

    Google Scholar 

  16. McCartney AC, Banks JG, Clements GB, Sleigh JD, Tehrani M, Ledingham JM (1983) Endotoxemia in septic shock: clinical and post mortem correlations. Intens Care Med 9: 117–122

    Article  CAS  Google Scholar 

  17. Brandtzaeg P, Kierulf P, Gaustad P, Skulberg A, Bruun JN, Halvorsen S, Sorensen E (1989) Plasma endotoxin as a predictor of multiple organ failure and death in systemic meningococcal disease. J Infect Dis 159: 195–204

    Article  PubMed  CAS  Google Scholar 

  18. Danner RL, Elin RJ, Hosseini JM, Wesley RA, Reilly JM, Parillo JE (1991) Endotoxemia in human septic shock. Chest 99: 169–175

    Article  PubMed  CAS  Google Scholar 

  19. Ketchum PA, Parsonnet J, Stotts LS, Novitsky TJ, Schlain B, Bates DW (1997) Utiliza-tion of a chromogenic Limulus amebocyte lysate blood assay in a multi-center study of sepsis. J Endotox Res 4: 9–16

    Google Scholar 

  20. Ulevitch RJ, Johnston AR, Weinstein DB (1979) New function for high density lipoproteins: their participation in intravascular reactions of bacterial lipopolysaccharides (LPS). J Clin Invest 64: 1516–1524

    Article  PubMed  CAS  Google Scholar 

  21. Levine DM, Parker TS, Donnelly TM, Walsh A, Rubin AL (1993) In vivo protection against endotoxin by plasma high density lipoprotein. Proc Natl Acad Sci USA 90: 12040–12044

    Article  PubMed  CAS  Google Scholar 

  22. Pajkrt D, Doran JE, Koster F, Lerch PG, Arnet B, Van der Poll T, ten Cate JW, van Deventer SJH (1996) Antiinflammatory effects of reconstituted high-density lipoprotein during human endotoxemia. J Exp Med 185: 1601–1608

    Article  Google Scholar 

  23. Flegel WA, Wolpl A, Mannel DN, Northoff H (1989) Inhibition of endotoxin-induced activation of human monocytes by human lipoproteins. Infect Immun 57: 2237–2245

    PubMed  CAS  Google Scholar 

  24. Navab M, Hough GP, Van Lenten BJ, Berliner JA, Fogelman AM (1988) Low density lipoproteins transfer bacterial lipopolysaccharides across endothelial monolayers in a biologically active form. J Clin Invest 81: 601–605

    Article  PubMed  CAS  Google Scholar 

  25. Netea MG, Demacker PN, Kullberg BJ, Boerman OC, Verschueren I, Stalenhoef AF, Van der Meer JW (1997) Low-density lipoprotein receptor-deficient mice are protected against lethal endotoxemia and severe gram-negative infections. J Clin Invest 97: 1366–1372

    Article  Google Scholar 

  26. Morrison DC (1990) Diversity of mammalian macromolecules which bind to bacterial lipopolysaccharide. Excerpta Med Int Cong Ser 923: 183–189

    Google Scholar 

  27. Wright SD, Ramos RA, Tobias PS, Ulevitch RJ, Mathison JC (1990) CD14, a receptor for complexes of lipopolysaccharide (LPS) and LPS binding protein. Science 249: 1431–1433

    Article  PubMed  CAS  Google Scholar 

  28. Grunwald U, Kruger C, Schutt C (1993) Endotoxin-neutralizing capacity of soluble CD14 is a highly conserved specific function. Circ Shock 39: 220–225

    PubMed  CAS  Google Scholar 

  29. Hailman E, Lichtenstein HS, Wurfel MM, Miller DS, Johnson DA, Kelley M, Busse LA, Zukowski MM, Wright SD (1994) Lipopolysaccharide (LPS)-binding protein accelerates the binding of LPS to CD14. J Exp Med 179: 269–277

    Article  PubMed  CAS  Google Scholar 

  30. Goyert SM, Ferrero E, Rettig WJ, Yenamandra AK, Obata F, LeBeau MM (1988) The CD14 monocyte differentiation antigen maps to a region encoding growth factors and receptors. Science 239: 497–500

    Article  PubMed  CAS  Google Scholar 

  31. Durieux JJ, Vita N, Popescu O, Guette F, Calzadawack J, Munker R, Schmidt RE, Lupker J, Ferrara P, Ziegler-Heitbrock HWL, et al (1994) The two soluble forms of the lipopolysaccharide receptor, CD14: characterization and release by normal human monocytes. Eur J Immunol 24: 2006–2012

    Article  PubMed  CAS  Google Scholar 

  32. Frey EA, Miller DS, Jahr TG, Sundan A, Bazil V, Espevik T, Finlay BB, Wright SD (1992) Soluble CD14 participates in the response of cells to lipopolysaccharide. J Exp Med 176: 1665–1671

    Article  PubMed  CAS  Google Scholar 

  33. Pugin J, Schürer-Maly CC, Leturcq D, Moriarty A, Ulevitch RJ, Tobias PS (1993) Lipopolysaccharide activation of human endothelial and epithelial cells is mediated by lipopolysaccharide-binding protein and soluble CD14. Proc Natl Acad Sci USA 90: 2744–2748

    Article  PubMed  CAS  Google Scholar 

  34. Leturcq DJ, Moriarty AM, Talbott G, Winn RK, Martin TR, Ulevitch RJ (1996) Antibodies against CD14 protect primates from endotoxin-induced shock. J Clin Invest 98: 1533–1538

    Article  PubMed  CAS  Google Scholar 

  35. Ferrero E, Jiao D, Tsuberi BZ, Tesio L, Rong GW, Haziot A, Goyert SM (1993) Trans-genic mice expressing human CD14 are hypersensitive to lipopolysaccharide. Proc Natl Acad Sci USA 90: 2380–2384

    Article  PubMed  CAS  Google Scholar 

  36. Haziot A, Ferrero E, Kontgen F, Hijiya N, Yamamoto S, Silver J, Stewart CL, Goyert SM (1996) Resistance to endotoxin shock and reduced dissemination of gram negative bacteria in CD14 deficient mice. Immunity 4: 407–414

    Article  PubMed  CAS  Google Scholar 

  37. Haziot A, Rong GW, Lin XY, Silver J, Goyert SM (1995) Recombinant soluble CD14 prevents mortality in mice treated with endotoxin (lipopolysaccharide). J Immunol 154: 6529–6532

    PubMed  CAS  Google Scholar 

  38. Tobias PS, Soldau K, Ulevitch RJ (1989) Identification of a lipid A binding site in the acute phase reactant lipopolysaccharide binding protein. J Biol Chem 264: 10867–10871

    PubMed  CAS  Google Scholar 

  39. Schumann RR, Kirschning C, Unbehaun A, Aberle H, Knopf HP, Ulevitch RJ, Herrmann F (1996) Lipopolysaccharide binding protein (LBP) is a secretory class 1 acute phase protein requiring binding of the transcription factor STAT-3, C/EBPb, and AP-1. Mol Cell Biol 16: 3490–3503

    PubMed  CAS  Google Scholar 

  40. Kirschning C, Unbehaun A, Lamping N, Pfeil D, Herrmann F, Schumann RR (1997) Control of transcriptional activation of the lipopolysaccharide binding protein (LBP) gene by pro-inflammatory cytokines. Cyt Mol Therapy 3: 59–62

    CAS  Google Scholar 

  41. Kirschning CJ, Hallatschek W, Lamping N, Reuter D, Pfeil D, Schumann RR (1997) Transcriptional activation of the acute phase protein lipopolysaccharide binding protein (LBP) involves transcription factors (STAT-3, C/EBP, and AP-1). In: E Faist (ed): The immune consequences of trauma,shock and sepsis. Mechanisms and therapeutic approaches. Monduzzi Editore, Bologna, 807–810

    Google Scholar 

  42. Lamping N, Hoess A, Yu B, Park TC, Kirschning CJ, Pfeil D, Reuter D, Wright SD, Herrmann F, Schumann RR (1996) Effects of site directed mutagenesis of basic residues (Arg 94, Lys 95, Lys 99) of lipopolysaccharide (LPS) binding protein on binding and transfer of LPS and subsequent immune cell activation. J Immunol 157: 4648–4656

    PubMed  CAS  Google Scholar 

  43. Hailman E, Albers JJ, Wolfbauer G, Tu AY, Wright SD (1996) Neutralization and transfer of lipopolysaccharide by phospholipid transfer protein. J Biol Chem 271: 12172–12178

    Article  PubMed  CAS  Google Scholar 

  44. Park CT, Wright SD (1996) Plasma lipopolysaccharide-binding protein is found associated with a particle containing apolipoprotein A-I, phospholipid, and factor H-related proteins. J Biol Chem 271: 18054–18060

    Article  PubMed  CAS  Google Scholar 

  45. Agellon LB, Quinet EM, Gillette TG, Drayna DT, Brown ML, Tall AR (1990) Organization of the human cholesteryl ester transfer protein gene. Biochemistry 29: 1372–1376

    Article  PubMed  CAS  Google Scholar 

  46. Day JR, Albers JJ, Lofton-Day CE, Gilbert TL, Ching AFT, Grand FJ, O’Hara PJ, Mar-covina SM, Adolphson JL (1994) Complete cDNA encoding human phospholipid transfer protein from human endothelial cells. J Biol Chem 269: 9388–9391

    PubMed  CAS  Google Scholar 

  47. Hubaceck JA, Buchler C, Aslandinis C, Schmitz G (1997) The genomic organization of the genes for human lipopolysaccharide binding protein (LBP) and bactericidal permeability increasing protein (BPI) is highly conserved. Biochem Biophys Res Commun 236: 427–430

    Article  Google Scholar 

  48. Kirschning CJ, Au-Young J, Lamping N, Reuter D, Pfeil D, Seilhamer J, Schumann RR (1997) Similar organization of the lipopolysaccharide binding protein and phospholipid transfer protein (PLTP). Genes suggest a common gene family of lipid binding proteins. Genomics 46: 416–425

    Article  PubMed  CAS  Google Scholar 

  49. Mathison JC, Tobias PS, Wolfson E, Ulevitch RJ (1992) Plasma lipopolysaccharide (LPS) binding protein. A key component in macrophage recognition of gram negative LPS. J Immunol 149: 200–206

    PubMed  CAS  Google Scholar 

  50. Schumann RR, Leong SR, Flaggs GW, Gray PW, Wright SD, Mathison JC, Tobias PS, Ulevitch RJ (1990) Structure and function of lipopolysaccharide binding protein. Science 249: 1429–1431

    Article  PubMed  CAS  Google Scholar 

  51. Grunwald U, Fan XL, Jack RS, Workalemahu G, Kallies A, Stelter F, Schütt C (1996) Monocytes can phagocytose gram negative bacteria by a CD14 dependent mechanism. J Immunol 157: 4119–4125

    PubMed  CAS  Google Scholar 

  52. Gallay P, Heumann D, Le RD, Barras C, Glauser MP (1994) Mode of action of antilipopolysaccharide binding protein antibodies for prevention of endotoxemic shock in mice. Proc Natl Acad Sci USA 91: 7922–7926

    Article  PubMed  CAS  Google Scholar 

  53. Lamping N, Dettmer R, Schröder NWJ, Pfeil D, Hallatschek W, Burger R, Schumann RR (1998) LPS-binding protein protects mice from septic shock caused by LPS or gram-negative bacteria. J Clin Invest 101: 2065–2071

    Article  PubMed  CAS  Google Scholar 

  54. Jack RS, Fan X, Bernheiden M, Rune G, Ehlers M, Weber A, Kirsch G, Mentel R, Fürll B, Freudenberg M et al (1997) Lipopolysaccharide-binding protein is reguired to combat a murine gram-negative bacterial infection. Nature 389: 742–745

    Article  PubMed  CAS  Google Scholar 

  55. Wurfel MM, Monks BG, Ingalls R, Dedrick R, Delude R, Zhou D, Lamping N, Schumann RR, Thieringer R, Fenton MJ, et al (1997) Targeted delection of the LBP gene leads to profound suppression of LPS responses ex vivo while in vivo responses remain intact. J Exp Med 186: 2051–2056

    Article  PubMed  CAS  Google Scholar 

  56. Johnston CA, Greisman SE (1985) Mechanism of endotoxin tolerance. In: LB Hinshaw (ed): Handbook of endotoxin, Vol 2: Pathophysiology of endotoxin. Elsevier, Amsterdam, New York, Oxford, 359–391

    Google Scholar 

  57. Schade FU, Flach R, Flohé S, Majetschak M, Kreuzfelder E, Domínguez-Fernández E, Börgermann J, Reuter M, Obertacke U (1998) Endotoxin tolerance. Marcel Dekker Inc; in press

    Google Scholar 

  58. Flohé S, Heinrich PC, Schneider J, Wendel A, Flohe L (1991) Time course of IL-6 and TNF alpha release during endotoxin-induced endotoxin tolerance in rats. Biochem Pharmacol 41: 1607–1614

    Article  PubMed  Google Scholar 

  59. 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 

  60. Mackensen A, Galanos C, Wehr U, Engelhardt R (1992) Endotoxin tolerance: regulation of cytokine production and cellular changes in response to endotoxin application in cancer patients. Eur Cytokine Netw 3: 571–579

    PubMed  CAS  Google Scholar 

  61. Henricson BE, Neta R, Vogel SN (1991) An interleukin-1 receptor antagonist blocks lipopolysaccharide-induced colony-stimulating factor production and early endotoxin tolerance. Infect Immun 59: 1188–1191

    PubMed  CAS  Google Scholar 

  62. 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 

  63. Galanos C, Freudenberg M, Katschinski T, Salomoa R, Mossmann H Kumazawa Y (1992) Tumor necrosis factor and host response to endotoxin. In: JL Ryan, DC Morrison (eds): Bacterial endotoxic lipopolysaccharides. CRC Press, Boca Raton, 75–104

    Google Scholar 

  64. Mathison JC, Virca GD, Wolfson E, Tobias PS, Glaser K, Ulevitch RJ (1990) Adaptation to bacterial lipopolysaccharide controls lipopolysaccharide-induced tumor necrosis factor production in rabbit macrophages. J Clin Invest 85: 1108–1118

    Article  PubMed  CAS  Google Scholar 

  65. Freudenberg MA, Galanos C (1988) Induction of tolerance to lipopolysaccharide (LPS)D-galactosamine lethality by pretreatment with LPS is mediated by macrophages. Infect Immun 56: 1352–1357

    PubMed  CAS  Google Scholar 

  66. Schade FU, Schlegel J, Hofmann K, Brade H, Flach R (1996) Endotoxin-tolerant mice produce an inhibitor of tumor necrosis factor-synthesis. J Endotox Res 3: 455–462

    CAS  Google Scholar 

  67. Flach R, Schade FU (1997) Peritoneal macrophages from endotoxin-tolerant mice produce an inhibitor of tumor necrosis factor a synthesis and protect against endotoxin shock. J Endotox Res 4: 241–250

    CAS  Google Scholar 

  68. Zanetti G, Glauser MP, Baumgartner JD (1993) Anti-endotoxin antibodies and other inhibitors of endotoxin. New Horizons 1:110–119

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Klinische Forschergruppe “Schock und Multiorganversagen” der DFG, Zentrum für Chirurgie, Universitätsklinikum Essen, Hufelandstr. 55, D-45122, Essen, Germany

    F. Ulrich Schade, Regina Flach & Thomas Hirsch

  2. Institut für Mikrobiologie und Hygiene, Universitätsklinikum Charité, Medizinische Fakultät der Humboldt-Universität zu Berlin, Dorotheenstr. 96-98, D-10117, Berlin, Germany

    Ralph R. Schumann

Authors
  1. F. Ulrich Schade
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Regina Flach
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Thomas Hirsch
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ralph R. Schumann
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, Donaueschingenstrasse 13, A-1200, Vienna, Austria

    Heinz Redl  & Günther Schlag  & 

Rights and permissions

Reprints and permissions

Copyright information

© 1999 Springer Basel AG

About this chapter

Cite this chapter

Schade, F.U., Flach, R., Hirsch, T., Schumann, R.R. (1999). Endotoxin as an inducer of cytokines. In: Redl, H., Schlag, G. (eds) Cytokines in Severe Sepsis and Septic Shock. Progress in Inflammation Research. Birkhäuser, Basel. https://doi.org/10.1007/978-3-0348-8755-7_1

Download citation

  • DOI: https://doi.org/10.1007/978-3-0348-8755-7_1

  • Publisher Name: Birkhäuser, Basel

  • Print ISBN: 978-3-0348-9759-4

  • Online ISBN: 978-3-0348-8755-7

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation