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The American Journal of Pathology logoLink to The American Journal of Pathology
. 1993 Sep;143(3):794–803.

The Production of lnterleukin-1 Receptor Antagonist by Human Bronchogenic Carcinoma

Daniel R Smith, Steven L Kunkel, Theodore J Standiford, Stephen W Chensue, Mark W Rolfe, Mark B Orringer, Richard I Whyte, Marie D Burdick, Jean M Danforth, Andrew R Gilbert, Robert M Strieter
PMCID: PMC1887195  PMID: 8362978

Abstract

Bronchogenic carcinoma displays an aggressive clinical course that may reflect a capacity to evade host defenses. We postulated that tumors may elaborate interleukin-1 receptor antagonist protein (IRAP) to escape host interleukin-1-dependent responses. Homogenates of human bronchogenic lung tumors demonstrated significant increases of IRAP compared with normal lung tissue controls (n = 48). There was no significant difference in interleukin-1 β levels between tumor and normal lung tissue. Immunohistochemical staining localized IRAP to tumor cells. Semiquantitative pathological analysis demonstrated a modest inflammatory cell infiltrate with qualitative differences between tumors of different histology. Western blot analysis of tumor homogenates demonstrated several molecular weight forms of IRAP. Finally, antigenic IRAP was detected in supernatants of the human bronchogenic carcinoma cell line (A549) maintained in vitro. These findings illustrate the capacity of bronchogenic tumors to produce and secrete IRAP that may be important in tumor evasion of host defenses.

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Selected References

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  1. Arend W. P., Joslin F. G., Massoni R. J. Effects of immune complexes on production by human monocytes of interleukin 1 or an interleukin 1 inhibitor. J Immunol. 1985 Jun;134(6):3868–3875. [PubMed] [Google Scholar]
  2. Arend W. P., Welgus H. G., Thompson R. C., Eisenberg S. P. Biological properties of recombinant human monocyte-derived interleukin 1 receptor antagonist. J Clin Invest. 1990 May;85(5):1694–1697. doi: 10.1172/JCI114622. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bigler C. F., Norris D. A., Weston W. L., Arend W. P. Interleukin-1 receptor antagonist production by human keratinocytes. J Invest Dermatol. 1992 Jan;98(1):38–44. doi: 10.1111/1523-1747.ep12494196. [DOI] [PubMed] [Google Scholar]
  4. Carter D. B., Deibel M. R., Jr, Dunn C. J., Tomich C. S., Laborde A. L., Slightom J. L., Berger A. E., Bienkowski M. J., Sun F. F., McEwan R. N. Purification, cloning, expression and biological characterization of an interleukin-1 receptor antagonist protein. Nature. 1990 Apr 12;344(6267):633–638. doi: 10.1038/344633a0. [DOI] [PubMed] [Google Scholar]
  5. Dayer-Métroz M. D., Wollheim C. B., Seckinger P., Dayer J. M. A natural interleukin 1 (IL-1) inhibitor counteracts the inhibitory effect of IL-1 on insulin production in cultured rat pancreatic islets. J Autoimmun. 1989 Apr;2(2):163–171. doi: 10.1016/0896-8411(89)90152-2. [DOI] [PubMed] [Google Scholar]
  6. Dinarello C. A. An update on human interleukin-1: from molecular biology to clinical relevance. J Clin Immunol. 1985 Sep;5(5):287–297. doi: 10.1007/BF00918247. [DOI] [PubMed] [Google Scholar]
  7. Dinarello C. A. Biology of interleukin 1. FASEB J. 1988 Feb;2(2):108–115. [PubMed] [Google Scholar]
  8. Dinarello C. A. Interleukin-1 and interleukin-1 antagonism. Blood. 1991 Apr 15;77(8):1627–1652. [PubMed] [Google Scholar]
  9. Dinarello C. A. Interleukin-1 and the pathogenesis of the acute-phase response. N Engl J Med. 1984 Nov 29;311(22):1413–1418. doi: 10.1056/NEJM198411293112205. [DOI] [PubMed] [Google Scholar]
  10. Dripps D. J., Brandhuber B. J., Thompson R. C., Eisenberg S. P. Interleukin-1 (IL-1) receptor antagonist binds to the 80-kDa IL-1 receptor but does not initiate IL-1 signal transduction. J Biol Chem. 1991 Jun 5;266(16):10331–10336. [PubMed] [Google Scholar]
  11. Eisenberg S. P., Brewer M. T., Verderber E., Heimdal P., Brandhuber B. J., Thompson R. C. Interleukin 1 receptor antagonist is a member of the interleukin 1 gene family: evolution of a cytokine control mechanism. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5232–5236. doi: 10.1073/pnas.88.12.5232. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Eisenberg S. P., Evans R. J., Arend W. P., Verderber E., Brewer M. T., Hannum C. H., Thompson R. C. Primary structure and functional expression from complementary DNA of a human interleukin-1 receptor antagonist. Nature. 1990 Jan 25;343(6256):341–346. doi: 10.1038/343341a0. [DOI] [PubMed] [Google Scholar]
  13. Folkman J. How is blood vessel growth regulated in normal and neoplastic tissue? G.H.A. Clowes memorial Award lecture. Cancer Res. 1986 Feb;46(2):467–473. [PubMed] [Google Scholar]
  14. Granowitz E. V., Clark B. D., Mancilla J., Dinarello C. A. Interleukin-1 receptor antagonist competitively inhibits the binding of interleukin-1 to the type II interleukin-1 receptor. J Biol Chem. 1991 Aug 5;266(22):14147–14150. [PubMed] [Google Scholar]
  15. Hannum C. H., Wilcox C. J., Arend W. P., Joslin F. G., Dripps D. J., Heimdal P. L., Armes L. G., Sommer A., Eisenberg S. P., Thompson R. C. Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature. 1990 Jan 25;343(6256):336–340. doi: 10.1038/343336a0. [DOI] [PubMed] [Google Scholar]
  16. Haskill S., Martin G., Van Le L., Morris J., Peace A., Bigler C. F., Jaffe G. J., Hammerberg C., Sporn S. A., Fong S. cDNA cloning of an intracellular form of the human interleukin 1 receptor antagonist associated with epithelium. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3681–3685. doi: 10.1073/pnas.88.9.3681. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Henderson B., Thompson R. C., Hardingham T., Lewthwaite J. Inhibition of interleukin-1-induced synovitis and articular cartilage proteoglycan loss in the rabbit knee by recombinant human interleukin-1 receptor antagonist. Cytokine. 1991 May;3(3):246–249. doi: 10.1016/1043-4666(91)90023-7. [DOI] [PubMed] [Google Scholar]
  18. Henricson B. E., Neta R., Vogel S. N. An interleukin-1 receptor antagonist blocks lipopolysaccharide-induced colony-stimulating factor production and early endotoxin tolerance. Infect Immun. 1991 Mar;59(3):1188–1191. doi: 10.1128/iai.59.3.1188-1191.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. 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]
  20. 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]
  21. Lovett D., Kozan B., Hadam M., Resch K., Gemsa D. Macrophage cytotoxicity: interleukin 1 as a mediator of tumor cytostasis. J Immunol. 1986 Jan;136(1):340–347. [PubMed] [Google Scholar]
  22. McColl S. R., Paquin R., Ménard C., Beaulieu A. D. Human neutrophils produce high levels of the interleukin 1 receptor antagonist in response to granulocyte/macrophage colony-stimulating factor and tumor necrosis factor alpha. J Exp Med. 1992 Aug 1;176(2):593–598. doi: 10.1084/jem.176.2.593. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. McIntyre K. W., Stepan G. J., Kolinsky K. D., Benjamin W. R., Plocinski J. M., Kaffka K. L., Campen C. A., Chizzonite R. A., Kilian P. L. Inhibition of interleukin 1 (IL-1) binding and bioactivity in vitro and modulation of acute inflammation in vivo by IL-1 receptor antagonist and anti-IL-1 receptor monoclonal antibody. J Exp Med. 1991 Apr 1;173(4):931–939. doi: 10.1084/jem.173.4.931. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Moore S. A., Strieter R. M., Rolfe M. W., Standiford T. J., Burdick M. D., Kunkel S. L. Expression and regulation of human alveolar macrophage-derived interleukin-1 receptor antagonist. Am J Respir Cell Mol Biol. 1992 Jun;6(6):569–575. doi: 10.1165/ajrcmb/6.6.569. [DOI] [PubMed] [Google Scholar]
  25. Nathan C. F. Secretory products of macrophages. J Clin Invest. 1987 Feb;79(2):319–326. doi: 10.1172/JCI112815. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Onozaki K., Matsushima K., Aggarwal B. B., Oppenheim J. J. Human interleukin 1 is a cytocidal factor for several tumor cell lines. J Immunol. 1985 Dec;135(6):3962–3968. [PubMed] [Google Scholar]
  27. Pauli B. U., Knudson W. Tumor invasion: a consequence of destructive and compositional matrix alterations. Hum Pathol. 1988 Jun;19(6):628–639. doi: 10.1016/s0046-8177(88)80168-0. [DOI] [PubMed] [Google Scholar]
  28. Rilke F., Colnaghi M. I., Cascinelli N., Andreola S., Baldini M. T., Bufalino R., Della Porta G., Ménard S., Pierotti M. A., Testori A. Prognostic significance of HER-2/neu expression in breast cancer and its relationship to other prognostic factors. Int J Cancer. 1991 Aug 19;49(1):44–49. doi: 10.1002/ijc.2910490109. [DOI] [PubMed] [Google Scholar]
  29. Seckinger P., Klein-Nulend J., Alander C., Thompson R. C., Dayer J. M., Raisz L. G. Natural and recombinant human IL-1 receptor antagonists block the effects of IL-1 on bone resorption and prostaglandin production. J Immunol. 1990 Dec 15;145(12):4181–4184. [PubMed] [Google Scholar]
  30. Seckinger P., Lowenthal J. W., Williamson K., Dayer J. M., MacDonald H. R. A urine inhibitor of interleukin 1 activity that blocks ligand binding. J Immunol. 1987 Sep 1;139(5):1546–1549. [PubMed] [Google Scholar]
  31. Seckinger P., Yaron I., Meyer F. A., Yaron M., Dayer J. M. Modulation of the effects of interleukin-1 on glycosaminoglycan synthesis by the urine-derived interleukin-1 inhibitor, but not by interleukin-6. Arthritis Rheum. 1990 Dec;33(12):1807–1814. doi: 10.1002/art.1780331208. [DOI] [PubMed] [Google Scholar]
  32. Standiford T. J., Kunkel S. L., Basha M. A., Chensue S. W., Lynch J. P., 3rd, Toews G. B., Westwick J., Strieter R. M. Interleukin-8 gene expression by a pulmonary epithelial cell line. A model for cytokine networks in the lung. J Clin Invest. 1990 Dec;86(6):1945–1953. doi: 10.1172/JCI114928. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Takemura R., Werb Z. Secretory products of macrophages and their physiological functions. Am J Physiol. 1984 Jan;246(1 Pt 1):C1–C9. doi: 10.1152/ajpcell.1984.246.1.C1. [DOI] [PubMed] [Google Scholar]

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