Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1988 May;81(5):1384–1389. doi: 10.1172/JCI113467

Tumor necrosis factor can induce fever in rats without activating protein breakdown in muscle or lipolysis in adipose tissue.

I C Kettelhut 1, A L Goldberg 1
PMCID: PMC442568  PMID: 3163348

Abstract

Tumor necrosis factor (TNF, cachectin) is a macrophage product that has been suggested to signal the loss of body weight, the decrease in adipose tissue and muscle mass, and anorexia during infections or chronic illness. To test this possibility, young growing rats were injected subcutaneously or intraperitoneally with human or murine recombinant TNF. After 3-4 h, these animals developed a 1-2 degrees fever which lasted approximately 4 h. With repeated daily TNF injections for 5 d, the animals developed fevers similarly each day. In contrast, rats injected with endotoxin show a single febrile episode and then are tolerant to subsequent daily injections of endotoxin (but do not develop tolerance to TNF or interleukin-1). On the first day of TNF treatment, the rats did not grow, but on subsequent days, despite their fevers, they grew at similar rates as controls. Although the TNF-treated rats consumed slightly less food than control animals, the ratio of growth per amount of food intake was identical in the two groups. When rats are administered endotoxin, they develop a fever, and their muscles show increased protein degradation and prostaglandin (PG)E2 production. However, when fevers were induced with TNF, there was no change in muscle proteolysis or PGE2 production, and in adipose tissue no increase in basal or catecholamine-induced lipolysis. Also TNF addition in vitro did not enhance lipolysis in epididymal fat pads or proteolysis in soleus muscles. Thus, TNF treatment can induce fever without producing a catabolic state similar to that induced by endotoxin.

Full text

PDF
1384

Selected References

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

  1. Aggarwal B. B., Eessalu T. E., Hass P. E. Characterization of receptors for human tumour necrosis factor and their regulation by gamma-interferon. Nature. 1985 Dec 19;318(6047):665–667. doi: 10.1038/318665a0. [DOI] [PubMed] [Google Scholar]
  2. Aggarwal B. B., Kohr W. J., Hass P. E., Moffat B., Spencer S. A., Henzel W. J., Bringman T. S., Nedwin G. E., Goeddel D. V., Harkins R. N. Human tumor necrosis factor. Production, purification, and characterization. J Biol Chem. 1985 Feb 25;260(4):2345–2354. [PubMed] [Google Scholar]
  3. Baracos V., Rodemann H. P., Dinarello C. A., Goldberg A. L. Stimulation of muscle protein degradation and prostaglandin E2 release by leukocytic pyrogen (interleukin-1). A mechanism for the increased degradation of muscle proteins during fever. N Engl J Med. 1983 Mar 10;308(10):553–558. doi: 10.1056/NEJM198303103081002. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Beutler B., Mahoney J., Le Trang N., Pekala P., Cerami A. Purification of cachectin, a lipoprotein lipase-suppressing hormone secreted by endotoxin-induced RAW 264.7 cells. J Exp Med. 1985 May 1;161(5):984–995. doi: 10.1084/jem.161.5.984. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. 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]
  7. 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]
  8. 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]
  9. Daniel A. M., Taylor M. E., Kapadia B., MacLean L. D. Metabolism of prolonged shock. Adv Shock Res. 1983;9:19–30. [PubMed] [Google Scholar]
  10. Dayer J. M., Beutler B., Cerami A. Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E2 production by human synovial cells and dermal fibroblasts. J Exp Med. 1985 Dec 1;162(6):2163–2168. doi: 10.1084/jem.162.6.2163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dinarello C. A., Bernheim H. A. Ability of human leukocytic pyrogen to stimulate brain prostaglandin synthesis in vitro. J Neurochem. 1981 Sep;37(3):702–708. doi: 10.1111/j.1471-4159.1982.tb12544.x. [DOI] [PubMed] [Google Scholar]
  12. Dinarello C. A., Cannon J. G., Wolff S. M., Bernheim H. A., Beutler B., Cerami A., Figari I. S., Palladino M. A., Jr, O'Connor J. V. Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1. J Exp Med. 1986 Jun 1;163(6):1433–1450. doi: 10.1084/jem.163.6.1433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. 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]
  14. Filkins J. P. Monokines and the metabolic pathophysiology of septic shock. Fed Proc. 1985 Feb;44(2):300–304. [PubMed] [Google Scholar]
  15. Fransen L., Van der Heyden J., Ruysschaert R., Fiers W. Recombinant tumor necrosis factor: its effect and its synergism with interferon-gamma on a variety of normal and transformed human cell lines. Eur J Cancer Clin Oncol. 1986 Apr;22(4):419–426. doi: 10.1016/0277-5379(86)90107-0. [DOI] [PubMed] [Google Scholar]
  16. Fulks R. M., Li J. B., Goldberg A. L. Effects of insulin, glucose, and amino acids on protein turnover in rat diaphragm. J Biol Chem. 1975 Jan 10;250(1):290–298. [PubMed] [Google Scholar]
  17. Goldberg A. L., Martel S. B., Kushmerick M. J. In vitro preparations of the diaphragm and other skeletal muscles. Methods Enzymol. 1975;39:82–94. doi: 10.1016/s0076-6879(75)39012-5. [DOI] [PubMed] [Google Scholar]
  18. Haranaka K., Satomi N., Sakurai A. Antitumor activity of murine tumor necrosis factor (TNF) against transplanted murine tumors and heterotransplanted human tumors in nude mice. Int J Cancer. 1984 Aug 15;34(2):263–267. doi: 10.1002/ijc.2910340219. [DOI] [PubMed] [Google Scholar]
  19. Helson L., Green S., Carswell E., Old L. J. Effect of tumour necrosis factor on cultured human melanoma cells. Nature. 1975 Dec 25;258(5537):731–732. doi: 10.1038/258731a0. [DOI] [PubMed] [Google Scholar]
  20. Kettelhut I. C., Fiers W., Goldberg A. L. The toxic effects of tumor necrosis factor in vivo and their prevention by cyclooxygenase inhibitors. Proc Natl Acad Sci U S A. 1987 Jun;84(12):4273–4277. doi: 10.1073/pnas.84.12.4273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kull F. C., Jr, Cuatrecasas P. Preliminary characterization of the tumor cell cytotoxin in tumor necrosis serum. J Immunol. 1981 Apr;126(4):1279–1283. [PubMed] [Google Scholar]
  22. McCarthy D. O., Kluger M. J., Vander A. J. The role of fever in appetite suppression after endotoxin administration. Am J Clin Nutr. 1984 Aug;40(2):310–316. doi: 10.1093/ajcn/40.2.310. [DOI] [PubMed] [Google Scholar]
  23. Nawroth P. P., Bank I., Handley D., Cassimeris J., Chess L., Stern D. Tumor necrosis factor/cachectin interacts with endothelial cell receptors to induce release of interleukin 1. J Exp Med. 1986 Jun 1;163(6):1363–1375. doi: 10.1084/jem.163.6.1363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. 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]
  25. Patton J. S., Shepard H. M., Wilking H., Lewis G., Aggarwal B. B., Eessalu T. E., Gavin L. A., Grunfeld C. Interferons and tumor necrosis factors have similar catabolic effects on 3T3 L1 cells. Proc Natl Acad Sci U S A. 1986 Nov;83(21):8313–8317. doi: 10.1073/pnas.83.21.8313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Pekala P. H., Kawakami M., Angus C. W., Lane M. D., Cerami A. Selective inhibition of synthesis of enzymes for de novo fatty acid biosynthesis by an endotoxin-induced mediator from exudate cells. Proc Natl Acad Sci U S A. 1983 May;80(9):2743–2747. doi: 10.1073/pnas.80.9.2743. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Pekala P. H., Price S. R., Horn C. A., Hom B. E., Moss J., Cerami A. Model for cachexia in chronic disease: secretory products of endotoxin-stimulated macrophages induce a catabolic state in 3T3-L1 adipocytes. Trans Assoc Am Physicians. 1984;97:251–259. [PubMed] [Google Scholar]
  28. Price S. R., Olivecrona T., Pekala P. H. Regulation of lipoprotein lipase synthesis by recombinant tumor necrosis factor--the primary regulatory role of the hormone in 3T3-L1 adipocytes. Arch Biochem Biophys. 1986 Dec;251(2):738–746. doi: 10.1016/0003-9861(86)90384-x. [DOI] [PubMed] [Google Scholar]
  29. Rodemann H. P., Waxman L., Goldberg A. L. The stimulation of protein degradation in muscle by Ca2+ is mediated by prostaglandin E2 and does not require the calcium-activated protease. J Biol Chem. 1982 Aug 10;257(15):8716–8723. [PubMed] [Google Scholar]
  30. Shirai T., Yamaguchi H., Ito H., Todd C. W., Wallace R. B. Cloning and expression in Escherichia coli of the gene for human tumour necrosis factor. 1985 Feb 28-Mar 6Nature. 313(6005):803–806. doi: 10.1038/313803a0. [DOI] [PubMed] [Google Scholar]
  31. Tischler M. E., Desautels M., Goldberg A. L. Does leucine, leucyl-tRNA, or some metabolite of leucine regulate protein synthesis and degradation in skeletal and cardiac muscle? J Biol Chem. 1982 Feb 25;257(4):1613–1621. [PubMed] [Google Scholar]
  32. Torti F. M., Dieckmann B., Beutler B., Cerami A., Ringold G. M. A macrophage factor inhibits adipocyte gene expression: an in vitro model of cachexia. Science. 1985 Aug 30;229(4716):867–869. doi: 10.1126/science.3839597. [DOI] [PubMed] [Google Scholar]
  33. 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]
  34. Tsujimoto M., Vilcek J. Tumor necrosis factor receptors in HeLa cells and their regulation by interferon-gamma. J Biol Chem. 1986 Apr 25;261(12):5384–5388. [PubMed] [Google Scholar]
  35. WAALKES T. P., UDENFRIEND S. A fluorometric method for the estimation of tyrosine in plasma and tissues. J Lab Clin Med. 1957 Nov;50(5):733–736. [PubMed] [Google Scholar]
  36. Wang A. M., Creasey A. A., Ladner M. B., Lin L. S., Strickler J., Van Arsdell J. N., Yamamoto R., Mark D. F. Molecular cloning of the complementary DNA for human tumor necrosis factor. Science. 1985 Apr 12;228(4696):149–154. doi: 10.1126/science.3856324. [DOI] [PubMed] [Google Scholar]
  37. Williamson B. D., Carswell E. A., Rubin B. Y., Prendergast J. S., Old L. J. Human tumor necrosis factor produced by human B-cell lines: synergistic cytotoxic interaction with human interferon. Proc Natl Acad Sci U S A. 1983 Sep;80(17):5397–5401. doi: 10.1073/pnas.80.17.5397. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES