Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1993 Mar;67(3):514–521. doi: 10.1038/bjc.1993.96

Temporal sequence and cellular origin of interleukin-2 stimulated cytokine gene expression.

K A Saraya 1, F R Balkwill 1
PMCID: PMC1968251  PMID: 8439502

Abstract

A study of activation of the cytokine network by interleukin 2, IL-2, may provide a rationale for devising cytokine combination and cytokine antagonist treatments with increased anti-tumour efficacy and decreased toxicity. We have investigated the expression of mRNA for 13 cytokines and three transcription factors during in vitro culture of peripheral blood mononuclear cells, PBMC, with IL-2. A consistent pattern of induction was seen in nine individuals, with early (2-24 h) induction of IL-1 beta, IL-6, tumour necrosis factor, TNF, lymphotoxin, LT, and gro. TNF and LT mRNA was expressed continually throughout culture, but levels of mRNA for IL-1 beta, IL-6, and gro declined by 24-48 h. After 48 h, PBMC began to express mRNA for IFN-gamma, IL-5, GM-CSF, and M-CSF. At 15 min to 1 h post IL-2 mRNA for c-fos, c-jun, and c-myc, and TNF was induced in three individuals studied. IL-4, IFN-alpha, and IL-1 alpha mRNA was not detected. Only a minority of cells expressed mRNA for TNF, IL-1 beta, IL-6 and IFN-gamma, and monocytes were the main source. Levels of cytokine protein in culture supernatants mirrored the pattern of mRNA induction. This in vitro model shows clear parallels with the reported in vivo production of cytokines during IL-2 therapy, and may prove useful in designing new therapeutic strategies.

Full text

PDF
520

Images in this article

516Figure 1
on p.516
518Figure 2
on p.518
518Figure 3
on p.518

Selected References

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

  1. Aoki T., Kikuchi H., Miyatake S., Oda Y., Iwasaki K., Yamasaki T., Kinashi T., Honjo T. Interleukin 5 enhances interleukin 2-mediated lymphokine-activated killer activity. J Exp Med. 1989 Aug 1;170(2):583–588. doi: 10.1084/jem.170.2.583. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Belldegrun A., Kasid A., Uppenkamp M., Topalian S. L., Rosenberg S. A. Human tumor infiltrating lymphocytes. Analysis of lymphokine mRNA expression and relevance to cancer immunotherapy. J Immunol. 1989 Jun 15;142(12):4520–4526. [PubMed] [Google Scholar]
  3. Bertani A., Polentarutti N., Sica A., Rambaldi A., Mantovani A., Colotta F. Expression of c-jun protooncogene in human myelomonocytic cells. Blood. 1989 Oct;74(5):1811–1816. [PubMed] [Google Scholar]
  4. Blay J. Y., Bertoglio J., Fradelizi D., Chouaib S. Functional interactions of IL2 and TNF in the differentiation of LGL into LAK effectors. Int J Cancer. 1989 Oct 15;44(4):598–604. doi: 10.1002/ijc.2910440407. [DOI] [PubMed] [Google Scholar]
  5. Blay J. Y., Favrot M. C., Negrier S., Combaret V., Chouaib S., Mercatello A., Kaemmerlen P., Franks C. R., Philip T. Correlation between clinical response to interleukin 2 therapy and sustained production of tumor necrosis factor. Cancer Res. 1990 Apr 15;50(8):2371–2374. [PubMed] [Google Scholar]
  6. Boccoli G., Masciulli R., Ruggeri E. M., Carlini P., Giannella G., Montesoro E., Mastroberardino G., Isacchi G., Testa U., Calabresi F. Adoptive immunotherapy of human cancer: the cytokine cascade and monocyte activation following high-dose interleukin 2 bolus treatment. Cancer Res. 1990 Sep 15;50(18):5795–5800. [PubMed] [Google Scholar]
  7. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  8. Crump W. L., 3rd, Owen-Schaub L. B., Grimm E. A. Synergy of human recombinant interleukin 1 with interleukin 2 in the generation of lymphokine-activated killer cells. Cancer Res. 1989 Jan 1;49(1):149–153. [PubMed] [Google Scholar]
  9. Dhar R., Ellis R. W., Shih T. Y., Oroszlan S., Shapiro B., Maizel J., Lowy D., Scolnick E. Nucleotide sequence of the p21 transforming protein of Harvey murine sarcoma virus. Science. 1982 Sep 3;217(4563):934–936. doi: 10.1126/science.6287572. [DOI] [PubMed] [Google Scholar]
  10. Djeu J. Y., Heinbaugh J. A., Holden H. T., Herberman R. B. Role of macrophages in the augementation of mouse natural killer cell activity by poly I:C and interferon. J Immunol. 1979 Jan;122(1):182–188. [PubMed] [Google Scholar]
  11. Dustin M. L., Rothlein R., Bhan A. K., Dinarello C. A., Springer T. A. Induction by IL 1 and interferon-gamma: tissue distribution, biochemistry, and function of a natural adherence molecule (ICAM-1). J Immunol. 1986 Jul 1;137(1):245–254. [PubMed] [Google Scholar]
  12. Dutcher J. P., Creekmore S., Weiss G. R., Margolin K., Markowitz A. B., Roper M., Parkinson D., Ciobanu N., Fisher R. I., Boldt D. H. A phase II study of interleukin-2 and lymphokine-activated killer cells in patients with metastatic malignant melanoma. J Clin Oncol. 1989 Apr;7(4):477–485. doi: 10.1200/JCO.1989.7.4.477. [DOI] [PubMed] [Google Scholar]
  13. Espinoza-Delgado I., Ortaldo J. R., Winkler-Pickett R., Sugamura K., Varesio L., Longo D. L. Expression and role of p75 interleukin 2 receptor on human monocytes. J Exp Med. 1990 May 1;171(5):1821–1826. doi: 10.1084/jem.171.5.1821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Feinberg A. P., Vogelstein B. "A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity". Addendum. Anal Biochem. 1984 Feb;137(1):266–267. doi: 10.1016/0003-2697(84)90381-6. [DOI] [PubMed] [Google Scholar]
  15. Fraker D. L., Langstein H. N., Norton J. A. Passive immunization against tumor necrosis factor partially abrogates interleukin 2 toxicity. J Exp Med. 1989 Sep 1;170(3):1015–1020. doi: 10.1084/jem.170.3.1015. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gaffney E. V., Tsai S. C. Lymphocyte-activating and growth-inhibitory activities for several sources of native and recombinant interleukin 1. Cancer Res. 1986 Aug;46(8):3834–3837. [PubMed] [Google Scholar]
  17. Galandrini R., Cernetti C., Albi N., Dembech C., Terenzi A., Grignani F., Velardi A. Interleukin-6 is constitutively produced by human CTL clones and is required to maintain their cytolytic function. Cell Immunol. 1991 Nov;138(1):11–23. doi: 10.1016/0008-8749(91)90128-x. [DOI] [PubMed] [Google Scholar]
  18. Gallagher G., Stimson W. H., Findlay J., al-Azzawi F. Interleukin-6 enhances the induction of human lymphokine-activated killer cells. Cancer Immunol Immunother. 1990;31(1):49–52. doi: 10.1007/BF01742495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Grimm E. A., Mazumder A., Zhang H. Z., Rosenberg S. A. Lymphokine-activated killer cell phenomenon. Lysis of natural killer-resistant fresh solid tumor cells by interleukin 2-activated autologous human peripheral blood lymphocytes. J Exp Med. 1982 Jun 1;155(6):1823–1841. doi: 10.1084/jem.155.6.1823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Imai K., Ng A. K., Glassy M. C., Ferrone S. Differential effect of interferon on the expression of tumor-associated antigens and histocompatibility antigens on human melanoma cells: relationship to susceptibility to immune lysis mediated by monoclonal antibodies. J Immunol. 1981 Aug;127(2):505–509. [PubMed] [Google Scholar]
  21. Kaczmarek L., Kamińska B. Molecular biology of cell activation. Exp Cell Res. 1989 Jul;183(1):24–35. doi: 10.1016/0014-4827(89)90415-1. [DOI] [PubMed] [Google Scholar]
  22. Kasid A., Director E. P., Rosenberg S. A. Induction of endogenous cytokine-mRNA in circulating peripheral blood mononuclear cells by IL-2 administration to cancer patients. J Immunol. 1989 Jul 15;143(2):736–739. [PubMed] [Google Scholar]
  23. Kelly S. A., Malik S. T., Balkwill F. R. The relevance of animal tumour models to the preclinical screening of cytokines. Cancer Surv. 1989;8(4):741–754. [PubMed] [Google Scholar]
  24. Kohler P. C., Sondel P. M. The role of interleukin-2 in cancer therapy. Cancer Surv. 1989;8(4):861–873. [PubMed] [Google Scholar]
  25. Kovacs E. J., Beckner S. K., Longo D. L., Varesio L., Young H. A. Cytokine gene expression during the generation of human lymphokine-activated killer cells: early induction of interleukin 1 beta by interleukin 2. Cancer Res. 1989 Feb 15;49(4):940–944. [PubMed] [Google Scholar]
  26. List J., Moser R. P., Steuer M., Loudon W. G., Blacklock J. B., Grimm E. A. Cytokine responses to intraventricular injection of interleukin 2 into patients with leptomeningeal carcinomatosis: rapid induction of tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, gamma-interferon, and soluble interleukin 2 receptor (Mr 55,000 protein). Cancer Res. 1992 Mar 1;52(5):1123–1128. [PubMed] [Google Scholar]
  27. Mulé J. J., McIntosh J. K., Jablons D. M., Rosenberg S. A. Antitumor activity of recombinant interleukin 6 in mice. J Exp Med. 1990 Mar 1;171(3):629–636. doi: 10.1084/jem.171.3.629. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Nakamura Y., Ozaki T., Yanagawa H., Yasuoka S., Ogura T. Eosinophil colony-stimulating factor induced by administration of interleukin-2 into the pleural cavity of patients with malignant pleurisy. Am J Respir Cell Mol Biol. 1990 Oct;3(4):291–300. doi: 10.1165/ajrcmb/3.4.291. [DOI] [PubMed] [Google Scholar]
  29. Naylor M. S., Stamp G. W., Balkwill F. R. Investigation of cytokine gene expression in human colorectal cancer. Cancer Res. 1990 Jul 15;50(14):4436–4440. [PubMed] [Google Scholar]
  30. Negrier S., Philip T., Stoter G., Fossa S. D., Janssen S., Iacone A., Cleton F. S., Eremin O., Israel L., Jasmin C. Interleukin-2 with or without LAK cells in metastatic renal cell carcinoma: a report of a European multicentre study. Eur J Cancer Clin Oncol. 1989;25 (Suppl 3):S21–S28. [PubMed] [Google Scholar]
  31. Numerof R. P., Aronson F. R., Mier J. W. IL-2 stimulates the production of IL-1 alpha and IL-1 beta by human peripheral blood mononuclear cells. J Immunol. 1988 Dec 15;141(12):4250–4257. [PubMed] [Google Scholar]
  32. Rangnekar V. V., Waheed S., Davies T. J., Toback F. G., Rangnekar V. M. Antimitogenic and mitogenic actions of interleukin-1 in diverse cell types are associated with induction of gro gene expression. J Biol Chem. 1991 Feb 5;266(4):2415–2422. [PubMed] [Google Scholar]
  33. Rosenberg S. A., Mulé J. J., Spiess P. J., Reichert C. M., Schwarz S. L. Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin 2. J Exp Med. 1985 May 1;161(5):1169–1188. doi: 10.1084/jem.161.5.1169. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Sacchi M., Snyderman C. H., Heo D. S., Johnson J. T., d'Amico F., Herberman R. B., Whiteside T. L. Local adoptive immunotherapy of human head and neck cancer xenografts in nude mice with lymphokine-activated killer cells and interleukin 2. Cancer Res. 1990 May 15;50(10):3113–3118. [PubMed] [Google Scholar]
  35. Schaafsma M. R., Falkenburg J. H., Landegent J. E., Duinkerken N., Osanto S., Ralph P., Kaushansky K., Wagemaker G., Van Damme J., Willemze R. In vivo production of interleukin-5, granulocyte-macrophage colony-stimulating factor, macrophages colony-stimulating factor, and interleukin-6 during intravenous administration of high-dose interleukin-2 in cancer patients. Blood. 1991 Oct 15;78(8):1981–1987. [PubMed] [Google Scholar]
  36. Smyth M. J., Ortaldo J. R., Bere W., Yagita H., Okumura K., Young H. A. IL-2 and IL-6 synergize to augment the pore-forming protein gene expression and cytotoxic potential of human peripheral blood T cells. J Immunol. 1990 Aug 15;145(4):1159–1166. [PubMed] [Google Scholar]
  37. Truitt G. A., Brunda M. J., Levitt D., Anderson T. D., Sherman M. I. The therapeutic activity in cancer of IL-2 in combination with other cytokines. Cancer Surv. 1989;8(4):875–889. [PubMed] [Google Scholar]
  38. Vieira P., de Waal-Malefyt R., Dang M. N., Johnson K. E., Kastelein R., Fiorentino D. F., deVries J. E., Roncarolo M. G., Mosmann T. R., Moore K. W. Isolation and expression of human cytokine synthesis inhibitory factor cDNA clones: homology to Epstein-Barr virus open reading frame BCRFI. Proc Natl Acad Sci U S A. 1991 Feb 15;88(4):1172–1176. doi: 10.1073/pnas.88.4.1172. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Waldmann T. A. The interleukin-2 receptor. J Biol Chem. 1991 Feb 15;266(5):2681–2684. [PubMed] [Google Scholar]
  40. Weber J. S., Rosenberg S. A. Effects of murine tumor class I major histocompatibility complex expression on antitumor activity of tumor-infiltrating lymphocytes. J Natl Cancer Inst. 1990 May 2;82(9):755–761. doi: 10.1093/jnci/82.9.755. [DOI] [PubMed] [Google Scholar]
  41. Yamaguchi Y., Suda T., Shiozaki H., Miura Y., Hitoshi Y., Tominaga A., Takatsu K., Kasahara T. Role of IL-5 in IL-2-induced eosinophilia. In vivo and in vitro expression of IL-5 mRNA by IL-2. J Immunol. 1990 Aug 1;145(3):873–877. [PubMed] [Google Scholar]
  42. de Waal Malefyt R., Abrams J., Bennett B., Figdor C. G., de Vries J. E. Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med. 1991 Nov 1;174(5):1209–1220. doi: 10.1084/jem.174.5.1209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. van Haelst Pisani C., Kovach J. S., Kita H., Leiferman K. M., Gleich G. J., Silver J. E., Dennin R., Abrams J. S. Administration of interleukin-2 (IL-2) results in increased plasma concentrations of IL-5 and eosinophilia in patients with cancer. Blood. 1991 Sep 15;78(6):1538–1544. [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES