Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1992 Sep;90(3):693–698. doi: 10.1172/JCI115939

The tissue distribution of tumor necrosis factor biosynthesis during endotoxemia.

B P Giroir 1, J H Johnson 1, T Brown 1, G L Allen 1, B Beutler 1
PMCID: PMC329918  PMID: 1522226

Abstract

Tumor necrosis factor (TNF) is a protein hormone implicated in the development of septic shock and other pathologic states. However, complexities inherent in detecting TNF synthesis by individual tissues have left the precise origins of this protein undefined. In addition, the possibility that localized TNF production may contribute to the pathogenesis of organ-specific diseases such as type I diabetes has not been explored in vivo. We have developed a transgenic mouse line bearing a reporter gene construct in which the TNF coding sequence and introns are replaced by a chloramphenicol acetyltransferase (CAT) coding sequence. In normal transgenic animals, CAT activity is expressed only in the thymus. When endotoxin is administered to the animals, CAT activity is also evident in kidney, heart, islets of Langerhans, spleen, lung, fallopian tubes, and uterus, but not in other organs. The biosynthesis of CAT in vivo correlated with tissue capacity to secrete TNF in vitro. Thus, TNF was secreted by all the tissues that expressed CAT, including lung, spleen, thymus, uterus/fallopian tubes, pancreatic islets, renal glomeruli, and cultured cardiac cells after exposure to endotoxin.

Full text

PDF
693

Images in this article

694Image
on p.694
695Image
on p.695

Selected References

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

  1. Baud L., Oudinet J. P., Bens M., Noe L., Peraldi M. N., Rondeau E., Etienne J., Ardaillou R. Production of tumor necrosis factor by rat mesangial cells in response to bacterial lipopolysaccharide. Kidney Int. 1989 May;35(5):1111–1118. doi: 10.1038/ki.1989.98. [DOI] [PubMed] [Google Scholar]
  2. Bendtzen K., Mandrup-Poulsen T., Nerup J., Nielsen J. H., Dinarello C. A., Svenson M. Cytotoxicity of human pI 7 interleukin-1 for pancreatic islets of Langerhans. Science. 1986 Jun 20;232(4757):1545–1547. doi: 10.1126/science.3086977. [DOI] [PubMed] [Google Scholar]
  3. Beutler B., Brown T. A CAT reporter construct allows ultrasensitive estimation of TNF synthesis, and suggests that the TNF gene has been silenced in non-macrophage cell lines. J Clin Invest. 1991 Apr;87(4):1336–1344. doi: 10.1172/JCI115137. [DOI] [PMC free article] [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. Boswell J. M., Yui M. A., Burt D. W., Kelley V. E. Increased tumor necrosis factor and IL-1 beta gene expression in the kidneys of mice with lupus nephritis. J Immunol. 1988 Nov 1;141(9):3050–3054. [PubMed] [Google Scholar]
  6. Campbell I. L., Cutri A., Wilson A., Harrison L. C. Evidence for IL-6 production by and effects on the pancreatic beta-cell. J Immunol. 1989 Aug 15;143(4):1188–1191. [PubMed] [Google Scholar]
  7. Campbell I. L., Kay T. W., Oxbrow L., Harrison L. C. Essential role for interferon-gamma and interleukin-6 in autoimmune insulin-dependent diabetes in NOD/Wehi mice. J Clin Invest. 1991 Feb;87(2):739–742. doi: 10.1172/JCI115055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Casey M. L., Cox S. M., Beutler B., Milewich L., MacDonald P. C. Cachectin/tumor necrosis factor-alpha formation in human decidua. Potential role of cytokines in infection-induced preterm labor. J Clin Invest. 1989 Feb;83(2):430–436. doi: 10.1172/JCI113901. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cerami A., Ikeda Y., Le Trang N., Hotez P. J., Beutler B. Weight loss associated with an endotoxin-induced mediator from peritoneal macrophages: the role of cachectin (tumor necrosis factor). Immunol Lett. 1985;11(3-4):173–177. doi: 10.1016/0165-2478(85)90165-8. [DOI] [PubMed] [Google Scholar]
  10. Chang H. R., Grau G. E., Pechère J. C. Role of TNF and IL-1 in infections with Toxoplasma gondii. Immunology. 1990 Jan;69(1):33–37. [PMC free article] [PubMed] [Google Scholar]
  11. Chensue S. W., Terebuh P. D., Remick D. G., Scales W. E., Kunkel S. L. In vivo biologic and immunohistochemical analysis of interleukin-1 alpha, beta and tumor necrosis factor during experimental endotoxemia. Kinetics, Kupffer cell expression, and glucocorticoid effects. Am J Pathol. 1991 Feb;138(2):395–402. [PMC free article] [PubMed] [Google Scholar]
  12. Chollet-Martin S., Depoix J. P., Hvass U., Pansard Y., Vissuzaine C., Gougerot-Pocidalo M. A. Raised plasma levels of tumor necrosis factor in heart allograft rejection. Transplant Proc. 1990 Feb;22(1):283–286. [PubMed] [Google Scholar]
  13. Colletti L. M., Burtch G. D., Remick D. G., Kunkel S. L., Strieter R. M., Guice K. S., Oldham K. T., Campbell D. A., Jr The production of tumor necrosis factor alpha and the development of a pulmonary capillary injury following hepatic ischemia/reperfusion. Transplantation. 1990 Feb;49(2):268–272. doi: 10.1097/00007890-199002000-00008. [DOI] [PubMed] [Google Scholar]
  14. Colletti L. M., Remick D. G., Burtch G. D., Kunkel S. L., Strieter R. M., Campbell D. A., Jr Role of tumor necrosis factor-alpha in the pathophysiologic alterations after hepatic ischemia/reperfusion injury in the rat. J Clin Invest. 1990 Jun;85(6):1936–1943. doi: 10.1172/JCI114656. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Cseh K., Beutler B. Alternative cleavage of the cachectin/tumor necrosis factor propeptide results in a larger, inactive form of secreted protein. J Biol Chem. 1989 Sep 25;264(27):16256–16260. [PubMed] [Google Scholar]
  16. Damas P., Reuter A., Gysen P., Demonty J., Lamy M., Franchimont P. Tumor necrosis factor and interleukin-1 serum levels during severe sepsis in humans. Crit Care Med. 1989 Oct;17(10):975–978. doi: 10.1097/00003246-198910000-00001. [DOI] [PubMed] [Google Scholar]
  17. Dhainaut J. F., Lanore J. J., de Gournay J. M., Huyghebaert M. F., Brunet F., Villemant D., Monsallier J. F. Right ventricular dysfunction in patients with septic shock. Intensive Care Med. 1988;14 (Suppl 2):488–491. doi: 10.1007/BF00256967. [DOI] [PubMed] [Google Scholar]
  18. Eizirik D. L. Interleukin-1 induced impairment in pancreatic islet oxidative metabolism of glucose is potentiated by tumor necrosis factor. Acta Endocrinol (Copenh) 1988 Nov;119(3):321–325. doi: 10.1530/acta.0.1190321. [DOI] [PubMed] [Google Scholar]
  19. Entman M. L., Youker K., Shappell S. B., Siegel C., Rothlein R., Dreyer W. J., Schmalstieg F. C., Smith C. W. Neutrophil adherence to isolated adult canine myocytes. Evidence for a CD18-dependent mechanism. J Clin Invest. 1990 May;85(5):1497–1506. doi: 10.1172/JCI114596. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Fong J. S., Drummond K. N. Method for preparation of glomeruli for metabolic studies. J Lab Clin Med. 1968 Jun;71(6):1034–1039. [PubMed] [Google Scholar]
  21. Girardin E., Grau G. E., Dayer J. M., Roux-Lombard P., Lambert P. H. Tumor necrosis factor and interleukin-1 in the serum of children with severe infectious purpura. N Engl J Med. 1988 Aug 18;319(7):397–400. doi: 10.1056/NEJM198808183190703. [DOI] [PubMed] [Google Scholar]
  22. Giroir B. P., Brown T., Beutler B. Constitutive synthesis of tumor necrosis factor in the thymus. Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):4864–4868. doi: 10.1073/pnas.89.11.4864. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Gorman C. M., Moffat L. F., Howard B. H. Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells. Mol Cell Biol. 1982 Sep;2(9):1044–1051. doi: 10.1128/mcb.2.9.1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. 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]
  25. Grau G. E., Taylor T. E., Molyneux M. E., Wirima J. J., Vassalli P., Hommel M., Lambert P. H. Tumor necrosis factor and disease severity in children with falciparum malaria. N Engl J Med. 1989 Jun 15;320(24):1586–1591. doi: 10.1056/NEJM198906153202404. [DOI] [PubMed] [Google Scholar]
  26. HARARY I., FARLEY B. In vitro studies of single isolated beating heart cells. Science. 1960 Jun 3;131(3414):1674–1675. doi: 10.1126/science.131.3414.1674. [DOI] [PubMed] [Google Scholar]
  27. Han J., Brown T., Beutler B. Endotoxin-responsive sequences control cachectin/tumor necrosis factor biosynthesis at the translational level. J Exp Med. 1990 Feb 1;171(2):465–475. doi: 10.1084/jem.171.2.465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Held W., MacDonald H. R., Weissman I. L., Hess M. W., Mueller C. Genes encoding tumor necrosis factor alpha and granzyme A are expressed during development of autoimmune diabetes. Proc Natl Acad Sci U S A. 1990 Mar;87(6):2239–2243. doi: 10.1073/pnas.87.6.2239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Horvath C. J., Ferro T. J., Jesmok G., Malik A. B. Recombinant tumor necrosis factor increases pulmonary vascular permeability independent of neutrophils. Proc Natl Acad Sci U S A. 1988 Dec;85(23):9219–9223. doi: 10.1073/pnas.85.23.9219. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Imagawa D. K., Millis J. M., Olthoff K. M., Derus L. J., Chia D., Sugich L. R., Ozawa M., Dempsey R. A., Iwaki Y., Levy P. J. The role of tumor necrosis factor in allograft rejection. I. Evidence that elevated levels of tumor necrosis factor-alpha predict rejection following orthotopic liver transplantation. Transplantation. 1990 Aug;50(2):219–225. doi: 10.1097/00007890-199008000-00009. [DOI] [PubMed] [Google Scholar]
  31. Jevnikar A. M., Wuthrich R. P., Brennan D. C., Maslinski W., Glimcher L. H., Rubin-Kelley V. E. TNF-alpha is expressed on the surface of kidney proximal tubular cells. Transplant Proc. 1991 Feb;23(1 Pt 1):231–232. [PubMed] [Google Scholar]
  32. Johnson J. H., Crider B. P., McCorkle K., Alford M., Unger R. H. Inhibition of glucose transport into rat islet cells by immunoglobulins from patients with new-onset insulin-dependent diabetes mellitus. N Engl J Med. 1990 Mar 8;322(10):653–659. doi: 10.1056/NEJM199003083221003. [DOI] [PubMed] [Google Scholar]
  33. Kindler V., Sappino A. P., Grau G. E., Piguet P. F., Vassalli P. The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection. Cell. 1989 Mar 10;56(5):731–740. doi: 10.1016/0092-8674(89)90676-4. [DOI] [PubMed] [Google Scholar]
  34. Kruys V., Kemmer K., Shakhov A., Jongeneel V., Beutler B. Constitutive activity of the tumor necrosis factor promoter is canceled by the 3' untranslated region in nonmacrophage cell lines; a trans-dominant factor overcomes this suppressive effect. Proc Natl Acad Sci U S A. 1992 Jan 15;89(2):673–677. doi: 10.1073/pnas.89.2.673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Lilly C. M., Sandhu J. S., Ishizaka A., Harada H., Yonemaru M., Larrick J. W., Shi T. X., O'Hanley P. T., Raffin T. A. Pentoxifylline prevents tumor necrosis factor-induced lung injury. Am Rev Respir Dis. 1989 Jun;139(6):1361–1368. doi: 10.1164/ajrccm/139.6.1361. [DOI] [PubMed] [Google Scholar]
  36. Mandrup-Poulsen T., Bendtzen K., Nerup J., Dinarello C. A., Svenson M., Nielsen J. H. Affinity-purified human interleukin I is cytotoxic to isolated islets of Langerhans. Diabetologia. 1986 Jan;29(1):63–67. doi: 10.1007/BF02427283. [DOI] [PubMed] [Google Scholar]
  37. Marks J. D., Marks C. B., Luce J. M., Montgomery A. B., Turner J., Metz C. A., Murray J. F. Plasma tumor necrosis factor in patients with septic shock. Mortality rate, incidence of adult respiratory distress syndrome, and effects of methylprednisolone administration. Am Rev Respir Dis. 1990 Jan;141(1):94–97. doi: 10.1164/ajrccm/141.1.94. [DOI] [PubMed] [Google Scholar]
  38. 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]
  39. Maury C. P., Teppo A. M. Circulating tumour necrosis factor-alpha (cachectin) in myocardial infarction. J Intern Med. 1989 May;225(5):333–336. doi: 10.1111/j.1365-2796.1989.tb00090.x. [DOI] [PubMed] [Google Scholar]
  40. 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]
  41. Mustafa M. M., Lebel M. H., Ramilo O., Olsen K. D., Reisch J. S., Beutler B., McCracken G. H., Jr Correlation of interleukin-1 beta and cachectin concentrations in cerebrospinal fluid and outcome from bacterial meningitis. J Pediatr. 1989 Aug;115(2):208–213. doi: 10.1016/s0022-3476(89)80067-8. [DOI] [PubMed] [Google Scholar]
  42. Mustafa M. M., Ramilo O., Sáez-Llorens X., Mertsola J., Magness R. R., McCracken G. H., Jr Prostaglandins E2 and I2, interleukin 1-beta, and tumor necrosis factor in cerebrospinal fluid in infants and children with bacterial meningitis. Pediatr Infect Dis J. 1989 Dec;8(12):921–922. doi: 10.1097/00006454-198912000-00045. [DOI] [PubMed] [Google Scholar]
  43. Mustafa M. M., Ramilo O., Sáez-Llorens X., Mertsola J., McCracken G. H., Jr Role of tumor necrosis factor alpha (cachectin) in experimental and clinical bacterial meningitis. Pediatr Infect Dis J. 1989 Dec;8(12):907–908. doi: 10.1097/00006454-198912000-00037. [DOI] [PubMed] [Google Scholar]
  44. Natanson C., Eichenholz P. W., Danner R. L., Eichacker P. Q., Hoffman W. D., Kuo G. C., Banks S. M., MacVittie T. J., Parrillo J. E. Endotoxin and tumor necrosis factor challenges in dogs simulate the cardiovascular profile of human septic shock. J Exp Med. 1989 Mar 1;169(3):823–832. doi: 10.1084/jem.169.3.823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Nelson S., Bagby G. J., Bainton B. G., Wilson L. A., Thompson J. J., Summer W. R. Compartmentalization of intraalveolar and systemic lipopolysaccharide-induced tumor necrosis factor and the pulmonary inflammatory response. J Infect Dis. 1989 Feb;159(2):189–194. doi: 10.1093/infdis/159.2.189. [DOI] [PubMed] [Google Scholar]
  46. Oliff A., Defeo-Jones D., Boyer M., Martinez D., Kiefer D., Vuocolo G., Wolfe A., Socher S. H. Tumors secreting human TNF/cachectin induce cachexia in mice. Cell. 1987 Aug 14;50(4):555–563. doi: 10.1016/0092-8674(87)90028-6. [DOI] [PubMed] [Google Scholar]
  47. Parrillo J. E., Burch C., Shelhamer J. H., Parker M. M., Natanson C., Schuette W. A circulating myocardial depressant substance in humans with septic shock. Septic shock patients with a reduced ejection fraction have a circulating factor that depresses in vitro myocardial cell performance. J Clin Invest. 1985 Oct;76(4):1539–1553. doi: 10.1172/JCI112135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Parrillo J. E., Parker M. M., Natanson C., Suffredini A. F., Danner R. L., Cunnion R. E., Ognibene F. P. Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med. 1990 Aug 1;113(3):227–242. doi: 10.7326/0003-4819-113-3-227. [DOI] [PubMed] [Google Scholar]
  49. Peppel K., Crawford D., Beutler B. A tumor necrosis factor (TNF) receptor-IgG heavy chain chimeric protein as a bivalent antagonist of TNF activity. J Exp Med. 1991 Dec 1;174(6):1483–1489. doi: 10.1084/jem.174.6.1483. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Piguet P. F., Collart M. A., Grau G. E., Kapanci Y., Vassalli P. Tumor necrosis factor/cachectin plays a key role in bleomycin-induced pneumopathy and fibrosis. J Exp Med. 1989 Sep 1;170(3):655–663. doi: 10.1084/jem.170.3.655. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Piguet P. F., Collart M. A., Grau G. E., Sappino A. P., Vassalli P. Requirement of tumour necrosis factor for development of silica-induced pulmonary fibrosis. Nature. 1990 Mar 15;344(6263):245–247. doi: 10.1038/344245a0. [DOI] [PubMed] [Google Scholar]
  52. Piguet P. F., Grau G. E., Allet B., Vassalli P. Tumor necrosis factor/cachectin is an effector of skin and gut lesions of the acute phase of graft-vs.-host disease. J Exp Med. 1987 Nov 1;166(5):1280–1289. doi: 10.1084/jem.166.5.1280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Ramilo O., Mustafa M. M., Porter J., Sáez-Llorens X., Mertsola J., Olsen K. D., Luby J. P., Beutler B., McCracken G. H., Jr Detection of interleukin 1 beta but not tumor necrosis factor-alpha in cerebrospinal fluid of children with aseptic meningitis. Am J Dis Child. 1990 Mar;144(3):349–352. doi: 10.1001/archpedi.1990.02150270099034. [DOI] [PubMed] [Google Scholar]
  54. Reilly J. M., Cunnion R. E., Burch-Whitman C., Parker M. M., Shelhamer J. H., Parrillo J. E. A circulating myocardial depressant substance is associated with cardiac dysfunction and peripheral hypoperfusion (lactic acidemia) in patients with septic shock. Chest. 1989 May;95(5):1072–1080. doi: 10.1378/chest.95.5.1072. [DOI] [PubMed] [Google Scholar]
  55. Sherry B. A., Gelin J., Fong Y., Marano M., Wei H., Cerami A., Lowry S. F., Lundholm K. G., Moldawer L. L. Anticachectin/tumor necrosis factor-alpha antibodies attenuate development of cachexia in tumor models. FASEB J. 1989 Jun;3(8):1956–1962. doi: 10.1096/fasebj.3.8.2721856. [DOI] [PubMed] [Google Scholar]
  56. Tabor D. R., Burchett S. K., Jacobs R. F. Enhanced production of monokines by canine alveolar macrophages in response to endotoxin-induced shock. Proc Soc Exp Biol Med. 1988 Apr;187(4):408–415. doi: 10.3181/00379727-187-42681. [DOI] [PubMed] [Google Scholar]
  57. Tovey M. G., Content J., Gresser I., Gugenheim J., Blanchard B., Guymarho J., Poupart P., Gigou M., Shaw A., Fiers W. Genes for IFN-beta-2 (IL-6), tumor necrosis factor, and IL-1 are expressed at high levels in the organs of normal individuals. J Immunol. 1988 Nov 1;141(9):3106–3110. [PubMed] [Google Scholar]
  58. 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]
  59. 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]
  60. Ulich T. R., Guo K. Z., Irwin B., Remick D. G., Davatelis G. N. Endotoxin-induced cytokine gene expression in vivo. II. Regulation of tumor necrosis factor and interleukin-1 alpha/beta expression and suppression. Am J Pathol. 1990 Nov;137(5):1173–1185. [PMC free article] [PubMed] [Google Scholar]
  61. 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]
  62. 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]
  63. Wright J. R., Jr, Epstein H. R., Hauptfeld V., Lacy P. E. Tumor necrosis factor enhances interferon-induced Ia antigen expression on murine islet parenchymal cells. Am J Pathol. 1988 Mar;130(3):427–430. [PMC free article] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES