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. 1990 Jan;136(1):49–60.

Role of tumor necrosis factor-alpha in lipopolysaccharide-induced pathologic alterations.

D G Remick 1, R M Strieter 1, M K Eskandari 1, D T Nguyen 1, M A Genord 1, C L Raiford 1, S L Kunkel 1
PMCID: PMC1877467  PMID: 2297050

Abstract

Tumor necrosis factor-alpha (TNF) has been implicated strongly as a principal mediator in the pathogenesis of septic shock. The authors investigated the in vivo production of TNF in CBA/J and CD-1 mice that had been primed by an intraperitoneal injection of complete Freund's adjuvant followed 2 weeks later by an intraperitoneal injection of lipopolysaccharide (LPS). TNF bioactivity peaked in both the ascites and plasma one hour after challenge, and TNF mRNA expression in the ascites cells peaked 30 minutes after LPS. After the induction of bioactivity, an interstitial pulmonary neutrophilic infiltrate occurred that was quantitated both morphometrically and by a myeloperoxidase (MPO) assay. Peripheral blood neutrophilia and lymphopenia developed after the LPS injection (PMNs: control, 46 +/- 2%; LPS, 65 +/- 3%; Lymphs control, 53 +/- 2%; LPS, 37 +/- 3%). Treatment with dexamethasone (Dex) completely inhibited the pulmonary neutrophilic infiltrate as measured by the (MPO) assay. Because Dex will inhibit the production of several cytokines, anti-TNF antiserum was given to mice at the same time as the LPS challenge to assess specifically the role of TNF in inducing these changes. This antiserum partially blocked the pulmonary neutrophil infiltrate, and completely blocked the peripheral blood changes at one hour after LPS. These data demonstrate that TNF plays an important role in the early pathophysiologic alterations that occur after systemic exposure to LPS.

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Selected References

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

  1. Besedovsky H., del Rey A., Sorkin E., Dinarello C. A. Immunoregulatory feedback between interleukin-1 and glucocorticoid hormones. Science. 1986 Aug 8;233(4764):652–654. doi: 10.1126/science.3014662. [DOI] [PubMed] [Google Scholar]
  2. Beutler B., Cerami A. Cachectin: more than a tumor necrosis factor. N Engl J Med. 1987 Feb 12;316(7):379–385. doi: 10.1056/NEJM198702123160705. [DOI] [PubMed] [Google Scholar]
  3. Beutler B., Cerami A. Tumor necrosis, cachexia, shock, and inflammation: a common mediator. Annu Rev Biochem. 1988;57:505–518. doi: 10.1146/annurev.bi.57.070188.002445. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. 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]
  6. Carswell E. A., Old L. J., Kassel R. L., Green S., Fiore N., Williamson B. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A. 1975 Sep;72(9):3666–3670. doi: 10.1073/pnas.72.9.3666. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Cerami A., Tracey K. J., Lowry S. F., Beutler B. Cachectin: a pluripotent hormone released during the host response to invasion. Recent Prog Horm Res. 1987;43:99–112. doi: 10.1016/b978-0-12-571143-2.50009-5. [DOI] [PubMed] [Google Scholar]
  8. Chensue S. W., Remick D. G., Shmyr-Forsch C., Beals T. F., Kunkel S. L. Immunohistochemical demonstration of cytoplasmic and membrane-associated tumor necrosis factor in murine macrophages. Am J Pathol. 1988 Dec;133(3):564–572. [PMC free article] [PubMed] [Google Scholar]
  9. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  10. Chong K. T., Huston M. Implications of endotoxin contamination in the evaluation of antibodies to lipopolysaccharides in a murine model of gram-negative sepsis. J Infect Dis. 1987 Nov;156(5):713–719. doi: 10.1093/infdis/156.5.713. [DOI] [PubMed] [Google Scholar]
  11. Espevik T., Nissen-Meyer J. A highly sensitive cell line, WEHI 164 clone 13, for measuring cytotoxic factor/tumor necrosis factor from human monocytes. J Immunol Methods. 1986 Dec 4;95(1):99–105. doi: 10.1016/0022-1759(86)90322-4. [DOI] [PubMed] [Google Scholar]
  12. Gale R. P., Opelz G., Golde D. W. The effect of endotoxin on circulating lymphocytes in normal man. Br J Haematol. 1977 May;36(1):49–58. doi: 10.1111/j.1365-2141.1977.tb05754.x. [DOI] [PubMed] [Google Scholar]
  13. Gilbert H. S., Rayfield E. J., Smith H., Jr, Keusch G. T. Effects of acute endotoxemia and glucose administration on circulating leukocyte populations in normal and diabetic subjects. Metabolism. 1978 Aug;27(8):889–899. doi: 10.1016/0026-0495(78)90132-4. [DOI] [PubMed] [Google Scholar]
  14. Goldblum S. E., Wu K. M., Jay M. Lung myeloperoxidase as a measure of pulmonary leukostasis in rabbits. J Appl Physiol (1985) 1985 Dec;59(6):1978–1985. doi: 10.1152/jappl.1985.59.6.1978. [DOI] [PubMed] [Google Scholar]
  15. Ha D. K., Leung S. W., Fung K. P., Choy Y. M., Lee C. Y. Production of tumour necrosis factor in Listeria monocytogenes-infected animals. Int J Immunopharmacol. 1985;7(1):1–6. doi: 10.1016/0192-0561(85)90002-5. [DOI] [PubMed] [Google Scholar]
  16. Harmsen A. G. Role of alveolar macrophages in lipopolysaccharide-induced neutrophil accumulation. Infect Immun. 1988 Aug;56(8):1858–1863. doi: 10.1128/iai.56.8.1858-1863.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Haslett C., Worthen G. S., Giclas P. C., Morrison D. C., Henson J. E., Henson P. M. The pulmonary vascular sequestration of neutrophils in endotoxemia is initiated by an effect of endotoxin on the neutrophil in the rabbit. Am Rev Respir Dis. 1987 Jul;136(1):9–18. doi: 10.1164/ajrccm/136.1.9. [DOI] [PubMed] [Google Scholar]
  18. Jonas E., Sargent T. D., Dawid I. B. Epidermal keratin gene expressed in embryos of Xenopus laevis. Proc Natl Acad Sci U S A. 1985 Aug;82(16):5413–5417. doi: 10.1073/pnas.82.16.5413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kunkel S. L., Spengler M., May M. A., Spengler R., Larrick J., Remick D. Prostaglandin E2 regulates macrophage-derived tumor necrosis factor gene expression. J Biol Chem. 1988 Apr 15;263(11):5380–5384. [PubMed] [Google Scholar]
  20. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  21. Le J., Vilcek J. Tumor necrosis factor and interleukin 1: cytokines with multiple overlapping biological activities. Lab Invest. 1987 Mar;56(3):234–248. [PubMed] [Google Scholar]
  22. Lähdevirta J., Maury C. P., Teppo A. M., Repo H. Elevated levels of circulating cachectin/tumor necrosis factor in patients with acquired immunodeficiency syndrome. Am J Med. 1988 Sep;85(3):289–291. doi: 10.1016/0002-9343(88)90576-1. [DOI] [PubMed] [Google Scholar]
  23. Mathison J. C., Wolfson E., Ulevitch R. J. Participation of tumor necrosis factor in the mediation of gram negative bacterial lipopolysaccharide-induced injury in rabbits. J Clin Invest. 1988 Jun;81(6):1925–1937. doi: 10.1172/JCI113540. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Matsushima K., Morishita K., Yoshimura T., Lavu S., Kobayashi Y., Lew W., Appella E., Kung H. F., Leonard E. J., Oppenheim J. J. Molecular cloning of a human monocyte-derived neutrophil chemotactic factor (MDNCF) and the induction of MDNCF mRNA by interleukin 1 and tumor necrosis factor. J Exp Med. 1988 Jun 1;167(6):1883–1893. doi: 10.1084/jem.167.6.1883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Maury C. P., Teppo A. M. Raised serum levels of cachectin/tumor necrosis factor alpha in renal allograft rejection. J Exp Med. 1987 Oct 1;166(4):1132–1137. doi: 10.1084/jem.166.4.1132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Michie H. R., Manogue K. R., Spriggs D. R., Revhaug A., O'Dwyer S., Dinarello C. A., Cerami A., Wolff S. M., Wilmore D. W. Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med. 1988 Jun 9;318(23):1481–1486. doi: 10.1056/NEJM198806093182301. [DOI] [PubMed] [Google Scholar]
  27. Mizel S. B., Oppenheim J. J., Rosenstreich D. L. Characterization of lymphocyte-activating factor (LAF) produced by the macrophage cell line, P388D1. I. Enhancement of LAF production by activated T lymphocytes. J Immunol. 1978 May;120(5):1497–1503. [PubMed] [Google Scholar]
  28. Morrison D. C. Bacterial endotoxins and pathogenesis. Rev Infect Dis. 1983 Sep-Oct;5 (Suppl 4):S733–S747. doi: 10.1093/clinids/5.supplement_4.s733. [DOI] [PubMed] [Google Scholar]
  29. Morrison D. C., Ulevitch R. J. The effects of bacterial endotoxins on host mediation systems. A review. Am J Pathol. 1978 Nov;93(2):526–618. [PMC free article] [PubMed] [Google Scholar]
  30. Pennica D., Nedwin G. E., Hayflick J. S., Seeburg P. H., Derynck R., Palladino M. A., Kohr W. J., Aggarwal B. B., Goeddel D. V. Human tumour necrosis factor: precursor structure, expression and homology to lymphotoxin. Nature. 1984 Dec 20;312(5996):724–729. doi: 10.1038/312724a0. [DOI] [PubMed] [Google Scholar]
  31. Remick D. G., Kunkel R. G., Larrick J. W., Kunkel S. L. Acute in vivo effects of human recombinant tumor necrosis factor. Lab Invest. 1987 Jun;56(6):583–590. [PubMed] [Google Scholar]
  32. Remick D. G., Larrick J., Kunkel S. L. Tumor necrosis factor-induced alterations in circulating leukocyte populations. Biochem Biophys Res Commun. 1986 Dec 15;141(2):818–824. doi: 10.1016/s0006-291x(86)80246-7. [DOI] [PubMed] [Google Scholar]
  33. Remick D. G., Scales W. E., May M. A., Spengler M., Nguyen D., Kunkel S. L. In situ hybridization analysis of macrophage-derived tumor necrosis factor and interleukin-1 mRNA. Lab Invest. 1988 Dec;59(6):809–816. [PubMed] [Google Scholar]
  34. Remick D. G., Strieter R. M., Lynch J. P., 3rd, Nguyen D., Eskandari M., Kunkel S. L. In vivo dynamics of murine tumor necrosis factor-alpha gene expression. Kinetics of dexamethasone-induced suppression. Lab Invest. 1989 Jun;60(6):766–771. [PubMed] [Google Scholar]
  35. Ruff M. R., Gifford G. E. Purification and physico-chemical characterization of rabbit tumor necrosis factor. J Immunol. 1980 Oct;125(4):1671–1677. [PubMed] [Google Scholar]
  36. Saxne T., Palladino M. A., Jr, Heinegård D., Talal N., Wollheim F. A. Detection of tumor necrosis factor alpha but not tumor necrosis factor beta in rheumatoid arthritis synovial fluid and serum. Arthritis Rheum. 1988 Aug;31(8):1041–1045. doi: 10.1002/art.1780310816. [DOI] [PubMed] [Google Scholar]
  37. 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]
  38. Snyder D. S., Unanue E. R. Corticosteroids inhibit murine macrophage Ia expression and interleukin 1 production. J Immunol. 1982 Nov;129(5):1803–1805. [PubMed] [Google Scholar]
  39. Stephens K. E., Ishizaka A., Larrick J. W., Raffin T. A. Tumor necrosis factor causes increased pulmonary permeability and edema. Comparison to septic acute lung injury. Am Rev Respir Dis. 1988 Jun;137(6):1364–1370. doi: 10.1164/ajrccm/137.6.1364. [DOI] [PubMed] [Google Scholar]
  40. Strieter R. M., Kunkel S. L., Showell H. J., Remick D. G., Phan S. H., Ward P. A., Marks R. M. Endothelial cell gene expression of a neutrophil chemotactic factor by TNF-alpha, LPS, and IL-1 beta. Science. 1989 Mar 17;243(4897):1467–1469. doi: 10.1126/science.2648570. [DOI] [PubMed] [Google Scholar]
  41. Tokunaga K., Taniguchi H., Yoda K., Shimizu M., Sakiyama S. Nucleotide sequence of a full-length cDNA for mouse cytoskeletal beta-actin mRNA. Nucleic Acids Res. 1986 Mar 25;14(6):2829–2829. doi: 10.1093/nar/14.6.2829. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. 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]
  43. Tracey K. J., Fong Y., Hesse D. G., Manogue K. R., Lee A. T., Kuo G. C., Lowry S. F., Cerami A. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature. 1987 Dec 17;330(6149):662–664. doi: 10.1038/330662a0. [DOI] [PubMed] [Google Scholar]
  44. Ulich T. R., Guo K., del Castillo J. Endotoxin-induced cytokine gene expression in vivo. I. Expression of tumor necrosis factor mRNA in visceral organs under physiologic conditions and during endotoxemia. Am J Pathol. 1989 Jan;134(1):11–14. [PMC free article] [PubMed] [Google Scholar]
  45. Ulich T. R., del Castillo J., Keys M., Granger G. A., Ni R. X. Kinetics and mechanisms of recombinant human interleukin 1 and tumor necrosis factor-alpha-induced changes in circulating numbers of neutrophils and lymphocytes. J Immunol. 1987 Nov 15;139(10):3406–3415. [PubMed] [Google Scholar]
  46. Uyttenhove C., Coulie P. G., Van Snick J. T cell growth and differentiation induced by interleukin-HP1/IL-6, the murine hybridoma/plasmacytoma growth factor. J Exp Med. 1988 Apr 1;167(4):1417–1427. doi: 10.1084/jem.167.4.1417. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Waage A., Brandtzaeg P., Halstensen A., Kierulf P., Espevik T. The complex pattern of cytokines in serum from patients with meningococcal septic shock. Association between interleukin 6, interleukin 1, and fatal outcome. J Exp Med. 1989 Jan 1;169(1):333–338. doi: 10.1084/jem.169.1.333. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Waage A., Espevik T. Interleukin 1 potentiates the lethal effect of tumor necrosis factor alpha/cachectin in mice. J Exp Med. 1988 Jun 1;167(6):1987–1992. doi: 10.1084/jem.167.6.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Waage A., Espevik T., Lamvik J. Detection of tumour necrosis factor-like cytotoxicity in serum from patients with septicaemia but not from untreated cancer patients. Scand J Immunol. 1986 Dec;24(6):739–743. doi: 10.1111/j.1365-3083.1986.tb02194.x. [DOI] [PubMed] [Google Scholar]
  50. 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]
  51. Worthen G. S., Haslett C., Rees A. J., Gumbay R. S., Henson J. E., Henson P. M. Neutrophil-mediated pulmonary vascular injury. Synergistic effect of trace amounts of lipopolysaccharide and neutrophil stimuli on vascular permeability and neutrophil sequestration in the lung. Am Rev Respir Dis. 1987 Jul;136(1):19–28. doi: 10.1164/ajrccm/136.1.19. [DOI] [PubMed] [Google Scholar]

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