Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1991 May 1;173(5):1177–1182. doi: 10.1084/jem.173.5.1177

Role of cytokines (interleukin 1, tumor necrosis factor, and transforming growth factor beta) in natural and lipopolysaccharide- enhanced radioresistance

PMCID: PMC2118844  PMID: 2022925

Abstract

Studies of radioresistance and radioprotection provide an excellent in vivo model for dissection of the pathophysiological role of cytokines. The availability of neutralizing antibodies to cytokines has made it possible to assess the contribution of cytokines to host defense and repair processes involved in radioresistance and radioprotection. Administration of anti-interleukin 1 receptor (IL-1R) antibody (35F5) or anti-tumor necrosis factor (TNF) antibody (TN3 19.12) reduced survival of irradiated CD2F1 mice. These results demonstrate conclusively that natural levels of IL-1 and TNF contribute to radioresistance of normal mice. Furthermore, the radioprotective effect of administered IL-1 was blocked not only with anti-IL-1R antibody but also with anti-TNF antibody. Similarly, the radioprotective effect of TNF was reduced with anti-IL-1R antibody. These data suggest that cooperative interaction of both cytokines is necessary to achieve successful radioprotection. Finally, when LPS was used as a radioprotector, the combined administration of anti-IL-1R and anti-TNF not only blocked the radioprotection with LPS, but actually revealed LPS to have a radiosensitizing effect. This effect may be due to induction of TGF-beta, since administration of this cytokine results in reduced survival of irradiated mice.

Full Text

The Full Text of this article is available as a PDF (552.6 KB).

Selected References

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

  1. AINSWORTH E. J., CHASE H. B. Effect of microbial antigens on irradiation mortality in mice. Proc Soc Exp Biol Med. 1959 Nov;102:483–485. doi: 10.3181/00379727-102-25290. [DOI] [PubMed] [Google Scholar]
  2. Assoian R. K., Fleurdelys B. E., Stevenson H. C., Miller P. J., Madtes D. K., Raines E. W., Ross R., Sporn M. B. Expression and secretion of type beta transforming growth factor by activated human macrophages. Proc Natl Acad Sci U S A. 1987 Sep;84(17):6020–6024. doi: 10.1073/pnas.84.17.6020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. 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]
  4. Chantry D., Turner M., Abney E., Feldmann M. Modulation of cytokine production by transforming growth factor-beta. J Immunol. 1989 Jun 15;142(12):4295–4300. [PubMed] [Google Scholar]
  5. Chizzonite R., Truitt T., Kilian P. L., Stern A. S., Nunes P., Parker K. P., Kaffka K. L., Chua A. O., Lugg D. K., Gubler U. Two high-affinity interleukin 1 receptors represent separate gene products. Proc Natl Acad Sci U S A. 1989 Oct;86(20):8029–8033. doi: 10.1073/pnas.86.20.8029. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. 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]
  7. Dinarello C. A. Interleukin-1 and its biologically related cytokines. Adv Immunol. 1989;44:153–205. doi: 10.1016/s0065-2776(08)60642-2. [DOI] [PubMed] [Google Scholar]
  8. Dubois C. M., Ruscetti F. W., Palaszynski E. W., Falk L. A., Oppenheim J. J., Keller J. R. Transforming growth factor beta is a potent inhibitor of interleukin 1 (IL-1) receptor expression: proposed mechanism of inhibition of IL-1 action. J Exp Med. 1990 Sep 1;172(3):737–744. doi: 10.1084/jem.172.3.737. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Ellingsworth L. R., Nakayama D., Segarini P., Dasch J., Carrillo P., Waegell W. Transforming growth factor-beta s are equipotent growth inhibitors of interleukin-1-induced thymocyte proliferation. Cell Immunol. 1988 Jun;114(1):41–54. doi: 10.1016/0008-8749(88)90253-5. [DOI] [PubMed] [Google Scholar]
  10. Espevik T., Figari I. S., Shalaby M. R., Lackides G. A., Lewis G. D., Shepard H. M., Palladino M. A., Jr Inhibition of cytokine production by cyclosporin A and transforming growth factor beta. J Exp Med. 1987 Aug 1;166(2):571–576. doi: 10.1084/jem.166.2.571. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gershenwald J. E., Fong Y. M., Fahey T. J., 3rd, Calvano S. E., Chizzonite R., Kilian P. L., Lowry S. F., Moldawer L. L. Interleukin 1 receptor blockade attenuates the host inflammatory response. Proc Natl Acad Sci U S A. 1990 Jul;87(13):4966–4970. doi: 10.1073/pnas.87.13.4966. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Hallahan D. E., Spriggs D. R., Beckett M. A., Kufe D. W., Weichselbaum R. R. Increased tumor necrosis factor alpha mRNA after cellular exposure to ionizing radiation. Proc Natl Acad Sci U S A. 1989 Dec;86(24):10104–10107. doi: 10.1073/pnas.86.24.10104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Keller J. R., Mantel C., Sing G. K., Ellingsworth L. R., Ruscetti S. K., Ruscetti F. W. Transforming growth factor beta 1 selectively regulates early murine hematopoietic progenitors and inhibits the growth of IL-3-dependent myeloid leukemia cell lines. J Exp Med. 1988 Aug 1;168(2):737–750. doi: 10.1084/jem.168.2.737. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Keller J. R., Mcniece I. K., Sill K. T., Ellingsworth L. R., Quesenberry P. J., Sing G. K., Ruscetti F. W. Transforming growth factor beta directly regulates primitive murine hematopoietic cell proliferation. Blood. 1990 Feb 1;75(3):596–602. [PubMed] [Google Scholar]
  15. Le J. M., Weinstein D., Gubler U., Vilcek J. Induction of membrane-associated interleukin 1 by tumor necrosis factor in human fibroblasts. J Immunol. 1987 Apr 1;138(7):2137–2142. [PubMed] [Google Scholar]
  16. 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]
  17. Metcalf D. Acute antigen-induced elevation of serum colony stimulating factor (CFS) levels. Immunology. 1971 Sep;21(3):427–436. [PMC free article] [PubMed] [Google Scholar]
  18. 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]
  19. Neta R., Douches S., Oppenheim J. J. Interleukin 1 is a radioprotector. J Immunol. 1986 Apr 1;136(7):2483–2485. [PubMed] [Google Scholar]
  20. Neta R., Oppenheim J. J. Cytokines in therapy of radiation injury. Blood. 1988 Sep;72(3):1093–1095. [PubMed] [Google Scholar]
  21. Neta R., Oppenheim J. J., Douches S. D. Interdependence of the radioprotective effects of human recombinant interleukin 1 alpha, tumor necrosis factor alpha, granulocyte colony-stimulating factor, and murine recombinant granulocyte-macrophage colony-stimulating factor. J Immunol. 1988 Jan 1;140(1):108–111. [PubMed] [Google Scholar]
  22. Neta R., Vogel S. N., Sipe J. D., Wong G. G., Nordan R. P. Comparison of in vivo effects of human recombinant IL 1 and human recombinant IL 6 in mice. Lymphokine Res. 1988 Winter;7(4):403–412. [PubMed] [Google Scholar]
  23. SMITH W. W., ALDERMAN I. M., GILLESPIE R. E. Increased survival in irradiated animals treated with bacterial endotoxins. Am J Physiol. 1957 Oct;191(1):124–130. doi: 10.1152/ajplegacy.1957.191.1.124. [DOI] [PubMed] [Google Scholar]
  24. Sheehan K. C., Ruddle N. H., Schreiber R. D. Generation and characterization of hamster monoclonal antibodies that neutralize murine tumor necrosis factors. J Immunol. 1989 Jun 1;142(11):3884–3893. [PubMed] [Google Scholar]
  25. Wahl S. M., Hunt D. A., Wong H. L., Dougherty S., McCartney-Francis N., Wahl L. M., Ellingsworth L., Schmidt J. A., Hall G., Roberts A. B. Transforming growth factor-beta is a potent immunosuppressive agent that inhibits IL-1-dependent lymphocyte proliferation. J Immunol. 1988 May 1;140(9):3026–3032. [PubMed] [Google Scholar]
  26. Woloschak G. E., Chang-Liu C. M., Jones P. S., Jones C. A. Modulation of gene expression in Syrian hamster embryo cells following ionizing radiation. Cancer Res. 1990 Jan 15;50(2):339–344. [PubMed] [Google Scholar]
  27. Youngner J. S., Stinebring W. R. Interferon appearance stimulated by endotoxin, bacteria, or viruses in mice pre-treated with Escherichia coli endotoxin or infected with Mycobacterium tuberculosis. Nature. 1965 Oct 30;208(5009):456–458. doi: 10.1038/208456a0. [DOI] [PubMed] [Google Scholar]

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

RESOURCES