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J Exp Med. 1991 May 1; 173(5): 1177–1182.
PMCID: PMC2118844

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

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.

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Selected References

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  • AINSWORTH EJ, CHASE HB. Effect of microbial antigens on irradiation mortality in mice. Proc Soc Exp Biol Med. 1959 Nov;102:483–485. [PubMed]
  • SMITH WW, ALDERMAN IM, GILLESPIE RE. Increased survival in irradiated animals treated with bacterial endotoxins. Am J Physiol. 1957 Oct;191(1):124–130. [PubMed]
  • Neta R, Douches S, Oppenheim JJ. Interleukin 1 is a radioprotector. J Immunol. 1986 Apr 1;136(7):2483–2485. [PubMed]
  • Neta R, Oppenheim JJ, Douches SD. 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]
  • Dinarello CA. Interleukin-1 and its biologically related cytokines. Adv Immunol. 1989;44:153–205. [PubMed]
  • Hallahan DE, Spriggs DR, Beckett MA, Kufe DW, Weichselbaum RR. 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. [PubMed]
  • Woloschak GE, Chang-Liu CM, Jones PS, Jones CA. Modulation of gene expression in Syrian hamster embryo cells following ionizing radiation. Cancer Res. 1990 Jan 15;50(2):339–344. [PubMed]
  • Chizzonite R, Truitt T, Kilian PL, Stern AS, Nunes P, Parker KP, Kaffka KL, Chua AO, Lugg DK, 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. [PubMed]
  • Sheehan KC, Ruddle NH, Schreiber RD. Generation and characterization of hamster monoclonal antibodies that neutralize murine tumor necrosis factors. J Immunol. 1989 Jun 1;142(11):3884–3893. [PubMed]
  • Le JM, 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]
  • Nawroth PP, 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. [PMC free article] [PubMed]
  • Assoian RK, Fleurdelys BE, Stevenson HC, Miller PJ, Madtes DK, Raines EW, Ross R, Sporn MB. 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. [PubMed]
  • Espevik T, Figari IS, Shalaby MR, Lackides GA, Lewis GD, Shepard HM, Palladino MA., Jr Inhibition of cytokine production by cyclosporin A and transforming growth factor beta. J Exp Med. 1987 Aug 1;166(2):571–576. [PMC free article] [PubMed]
  • Ellingsworth LR, 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. [PubMed]
  • Wahl SM, Hunt DA, Wong HL, Dougherty S, McCartney-Francis N, Wahl LM, Ellingsworth L, Schmidt JA, Hall G, Roberts AB, et al. 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]
  • Keller JR, Mantel C, Sing GK, Ellingsworth LR, Ruscetti SK, Ruscetti FW. 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. [PMC free article] [PubMed]
  • Keller JR, Mcniece IK, Sill KT, Ellingsworth LR, Quesenberry PJ, Sing GK, Ruscetti FW. Transforming growth factor beta directly regulates primitive murine hematopoietic cell proliferation. Blood. 1990 Feb 1;75(3):596–602. [PubMed]
  • Gershenwald JE, Fong YM, Fahey TJ, 3rd, Calvano SE, Chizzonite R, Kilian PL, Lowry SF, Moldawer LL. Interleukin 1 receptor blockade attenuates the host inflammatory response. Proc Natl Acad Sci U S A. 1990 Jul;87(13):4966–4970. [PubMed]
  • Neta R, Oppenheim JJ. Cytokines in therapy of radiation injury. Blood. 1988 Sep;72(3):1093–1095. [PubMed]
  • Dinarello CA, Cannon JG, Wolff SM, Bernheim HA, Beutler B, Cerami A, Figari IS, Palladino MA, Jr, O'Connor JV. Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1. J Exp Med. 1986 Jun 1;163(6):1433–1450. [PMC free article] [PubMed]
  • 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]
  • Carswell EA, Old LJ, Kassel RL, 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. [PubMed]
  • Metcalf D. Acute antigen-induced elevation of serum colony stimulating factor (CFS) levels. Immunology. 1971 Sep;21(3):427–436. [PubMed]
  • Youngner JS, Stinebring WR. 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. [PubMed]
  • 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]
  • Dubois CM, Ruscetti FW, Palaszynski EW, Falk LA, Oppenheim JJ, Keller JR. 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. [PMC free article] [PubMed]
  • Neta R, Vogel SN, Sipe JD, Wong GG, Nordan RP. 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]

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