Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1989 Jun 1;169(6):2021–2027. doi: 10.1084/jem.169.6.2021

Pretreatment with recombinant murine tumor necrosis factor alpha/cachectin and murine interleukin 1 alpha protects mice from lethal bacterial infection

PMCID: PMC2189352  PMID: 2659724

Abstract

Tumor necrosis factor/cachectin (TNF/C) is the principal mediator of bacterial endotoxin-induced shock and death. We found that the C3H/HeJ mouse, which is less able to produce TNF/C in response to endotoxin, has a 1,000-fold greater susceptibility to lethal infection with Escherichia coli than the TNF-responsive congenic mouse, C3H/HeN. This surprising finding suggested that this lethal peptide may also be involved in host protection. To test this hypothesis we pretreated the C3H/HeJ mouse with a combination of recombinant murine TNF/C-alpha and IL-1 alpha. This combination protected these mice against an intraperitoneal bacterial challenge of greater than 20 LD50S (nearly 2 x 10(2) CFU) that grew to a level of greater than 10(7) CFU/ml of blood and per gram of liver in untreated mice. This suggests a significant role for these cytokines in host defenses against invasive infections that require bacterial replication within the host. These protective mechanisms may not be important for less virulent organisms. These findings may have important implications for the proposed use of anti- TNF/C agents in the treatment of septic shock.

Full Text

The Full Text of this article is available as a PDF (488.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bachwich P. R., Lynch J. P., 3rd, Larrick J., Spengler M., Kunkel S. L. Tumor necrosis factor production by human sarcoid alveolar macrophages. Am J Pathol. 1986 Dec;125(3):421–425. [PMC free article] [PubMed] [Google Scholar]
  2. Beutler B., Cerami A. Cachectin and tumour necrosis factor as two sides of the same biological coin. Nature. 1986 Apr 17;320(6063):584–588. doi: 10.1038/320584a0. [DOI] [PubMed] [Google Scholar]
  3. Beutler B., Krochin N., Milsark I. W., Luedke C., Cerami A. Control of cachectin (tumor necrosis factor) synthesis: mechanisms of endotoxin resistance. Science. 1986 May 23;232(4753):977–980. doi: 10.1126/science.3754653. [DOI] [PubMed] [Google Scholar]
  4. Beutler B., Milsark I. W., Cerami A. C. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science. 1985 Aug 30;229(4716):869–871. doi: 10.1126/science.3895437. [DOI] [PubMed] [Google Scholar]
  5. Cannistra S. A., Rambaldi A., Spriggs D. R., Herrmann F., Kufe D., Griffin J. D. Human granulocyte-macrophage colony-stimulating factor induces expression of the tumor necrosis factor gene by the U937 cell line and by normal human monocytes. J Clin Invest. 1987 Jun;79(6):1720–1728. doi: 10.1172/JCI113012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Cross A. S., Gemski P., Sadoff J. C., Orskov F., Orskov I. The importance of the K1 capsule in invasive infections caused by Escherichia coli. J Infect Dis. 1984 Feb;149(2):184–193. doi: 10.1093/infdis/149.2.184. [DOI] [PubMed] [Google Scholar]
  7. Czuprynski C. J., Brown J. F. Recombinant murine interleukin-1 alpha enhancement of nonspecific antibacterial resistance. Infect Immun. 1987 Sep;55(9):2061–2065. doi: 10.1128/iai.55.9.2061-2065.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Denizot F., Lang R. Rapid colorimetric assay for cell growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. J Immunol Methods. 1986 May 22;89(2):271–277. doi: 10.1016/0022-1759(86)90368-6. [DOI] [PubMed] [Google Scholar]
  9. Dinarello C. A., Ikejima T., Warner S. J., Orencole S. F., Lonnemann G., Cannon J. G., Libby P. Interleukin 1 induces interleukin 1. I. Induction of circulating interleukin 1 in rabbits in vivo and in human mononuclear cells in vitro. J Immunol. 1987 Sep 15;139(6):1902–1910. [PubMed] [Google Scholar]
  10. Dinarello C. A. Interleukin-1. Rev Infect Dis. 1984 Jan-Feb;6(1):51–95. doi: 10.1093/clinids/6.1.51. [DOI] [PubMed] [Google Scholar]
  11. Esparza I., Männel D., Ruppel A., Falk W., Krammer P. H. Interferon gamma and lymphotoxin or tumor necrosis factor act synergistically to induce macrophage killing of tumor cells and schistosomula of Schistosoma mansoni. J Exp Med. 1987 Aug 1;166(2):589–594. doi: 10.1084/jem.166.2.589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fujiki T., Tanaka A. Antibacterial activity of recombinant murine beta interferon. Infect Immun. 1988 Mar;56(3):548–551. doi: 10.1128/iai.56.3.548-551.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Grau G. E., Fajardo L. F., Piguet P. F., Allet B., Lambert P. H., Vassalli P. Tumor necrosis factor (cachectin) as an essential mediator in murine cerebral malaria. Science. 1987 Sep 4;237(4819):1210–1212. doi: 10.1126/science.3306918. [DOI] [PubMed] [Google Scholar]
  14. Hesse D. G., Tracey K. J., Fong Y., Manogue K. R., Palladino M. A., Jr, Cerami A., Shires G. T., Lowry S. F. Cytokine appearance in human endotoxemia and primate bacteremia. Surg Gynecol Obstet. 1988 Feb;166(2):147–153. [PubMed] [Google Scholar]
  15. Iizawa Y., Nishi T., Kondo M., Tsuchiya K., Imada A. Effect of recombinant human interleukin-2 on the course of experimental chronic respiratory tract infection caused by Klebsiella pneumoniae in mice. Infect Immun. 1988 Jan;56(1):45–50. doi: 10.1128/iai.56.1.45-50.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Marmenout A., Fransen L., Tavernier J., Van der Heyden J., Tizard R., Kawashima E., Shaw A., Johnson M. J., Semon D., Müller R. Molecular cloning and expression of human tumor necrosis factor and comparison with mouse tumor necrosis factor. Eur J Biochem. 1985 Nov 4;152(3):515–522. doi: 10.1111/j.1432-1033.1985.tb09226.x. [DOI] [PubMed] [Google Scholar]
  17. Nakane A., Minagawa T., Kato K. Endogenous tumor necrosis factor (cachectin) is essential to host resistance against Listeria monocytogenes infection. Infect Immun. 1988 Oct;56(10):2563–2569. doi: 10.1128/iai.56.10.2563-2569.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Scuderi P., Sterling K. E., Lam K. S., Finley P. R., Ryan K. J., Ray C. G., Petersen E., Slymen D. J., Salmon S. E. Raised serum levels of tumour necrosis factor in parasitic infections. Lancet. 1986 Dec 13;2(8520):1364–1365. doi: 10.1016/s0140-6736(86)92007-6. [DOI] [PubMed] [Google Scholar]
  19. Shalaby M. R., Aggarwal B. B., Rinderknecht E., Svedersky L. P., Finkle B. S., Palladino M. A., Jr Activation of human polymorphonuclear neutrophil functions by interferon-gamma and tumor necrosis factors. J Immunol. 1985 Sep;135(3):2069–2073. [PubMed] [Google Scholar]
  20. Tracey K. J., Beutler B., Lowry S. F., Merryweather J., Wolpe S., Milsark I. W., Hariri R. J., Fahey T. J., 3rd, Zentella A., Albert J. D. Shock and tissue injury induced by recombinant human cachectin. Science. 1986 Oct 24;234(4775):470–474. doi: 10.1126/science.3764421. [DOI] [PubMed] [Google Scholar]
  21. Tracey K. J., Lowry S. F., Fahey T. J., 3rd, Albert J. D., Fong Y., Hesse D., Beutler B., Manogue K. R., Calvano S., Wei H. Cachectin/tumor necrosis factor induces lethal shock and stress hormone responses in the dog. Surg Gynecol Obstet. 1987 May;164(5):415–422. [PubMed] [Google Scholar]
  22. Urbaschek R., Urbaschek B. Tumor necrosis factor and interleukin 1 as mediators of endotoxin-induced beneficial effects. Rev Infect Dis. 1987 Sep-Oct;9 (Suppl 5):S607–S615. doi: 10.1093/clinids/9.supplement_5.s607. [DOI] [PubMed] [Google Scholar]
  23. Vogel S. N., Douches S. D., Kaufman E. N., Neta R. Induction of colony stimulating factor in vivo by recombinant interleukin 1 alpha and recombinant tumor necrosis factor alpha 1. J Immunol. 1987 Apr 1;138(7):2143–2148. [PubMed] [Google Scholar]
  24. Waage A., Halstensen A., Espevik T. Association between tumour necrosis factor in serum and fatal outcome in patients with meningococcal disease. Lancet. 1987 Feb 14;1(8529):355–357. doi: 10.1016/s0140-6736(87)91728-4. [DOI] [PubMed] [Google Scholar]
  25. Weisbart R. H., Golde D. W., Clark S. C., Wong G. G., Gasson J. C. Human granulocyte-macrophage colony-stimulating factor is a neutrophil activator. 1985 Mar 28-Apr 3Nature. 314(6009):361–363. doi: 10.1038/314361a0. [DOI] [PubMed] [Google Scholar]
  26. White C. W., Ghezzi P., Dinarello C. A., Caldwell S. A., McMurtry I. F., Repine J. E. Recombinant tumor necrosis factor/cachectin and interleukin 1 pretreatment decreases lung oxidized glutathione accumulation, lung injury, and mortality in rats exposed to hyperoxia. J Clin Invest. 1987 Jun;79(6):1868–1873. doi: 10.1172/JCI113029. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES