Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1989 Aug;84(2):451–457. doi: 10.1172/JCI114186

Participation of the cytokines interleukin 6, tumor necrosis factor-alpha, and interleukin 1-beta secreted by acute myelogenous leukemia blasts in autocrine and paracrine leukemia growth control.

W Oster 1, N A Cicco 1, H Klein 1, T Hirano 1, T Kishimoto 1, A Lindemann 1, R H Mertelsmann 1, F Herrmann 1
PMCID: PMC548903  PMID: 2788173

Abstract

Autonomous in vitro growth of myeloid leukemic colony-forming cells may in part result from autocrine production of colony-stimulating factors (CSF). Some acute myeloid leukemia (AML) samples, however, fail to synthesize CSF despite growing autonomously in agar, and are therefore believed to bypass CSF requirements. Cytokines such as IL-6, tumor necrosis factor (TNF)-alpha, and IL-1, products of cells of the myeloid lineage, are known to be involved in growth control of myeloid progenitor cells. Since these molecules may also contribute to autocrine and paracrine growth regulation of myeloid leukemias, we screened a series of AML for cytokine production. In addition, possible roles of IL-6, TNF-alpha, and IL-1 in growth control of AML were investigated in vitro. We show that a substantial proportion of AML cells produce IL-6, TNF-alpha, and IL-1-beta and use these mediators to stimulate their growth by disparate mechanisms: IL-6 acts as a costimulator to enhance CSF-induced clonogenicity of AML blasts. TNF-alpha induces CSF production by endothelial cells and may therefore provide a paracrine loop to support leukemia growth.

Full text

PDF
452

Images in this article

452Image
on p.452
454Image
on p.454

Selected References

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

  1. Aarden L. A., De Groot E. R., Schaap O. L., Lansdorp P. M. Production of hybridoma growth factor by human monocytes. Eur J Immunol. 1987 Oct;17(10):1411–1416. doi: 10.1002/eji.1830171004. [DOI] [PubMed] [Google Scholar]
  2. Bennett J. M., Catovsky D., Daniel M. T., Flandrin G., Galton D. A., Gralnick H. R., Sultan C. Proposals for the classification of the acute leukaemias. French-American-British (FAB) co-operative group. Br J Haematol. 1976 Aug;33(4):451–458. doi: 10.1111/j.1365-2141.1976.tb03563.x. [DOI] [PubMed] [Google Scholar]
  3. Buick R. N., Till J. E., McCulloch E. A. Colony assay for proliferative blast cells circulating in myeloblastic leukaemia. Lancet. 1977 Apr 16;1(8016):862–863. doi: 10.1016/s0140-6736(77)92818-5. [DOI] [PubMed] [Google Scholar]
  4. Clark S. C., Kamen R. The human hematopoietic colony-stimulating factors. Science. 1987 Jun 5;236(4806):1229–1237. doi: 10.1126/science.3296190. [DOI] [PubMed] [Google Scholar]
  5. Content J., De Wit L., Poupart P., Opdenakker G., Van Damme J., Billiau A. Induction of a 26-kDa-protein mRNA in human cells treated with an interleukin-1-related, leukocyte-derived factor. Eur J Biochem. 1985 Oct 15;152(2):253–257. doi: 10.1111/j.1432-1033.1985.tb09191.x. [DOI] [PubMed] [Google Scholar]
  6. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  7. Gauldie J., Richards C., Harnish D., Lansdorp P., Baumann H. Interferon beta 2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells. Proc Natl Acad Sci U S A. 1987 Oct;84(20):7251–7255. doi: 10.1073/pnas.84.20.7251. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Griffin J. D., Rambaldi A., Vellenga E., Young D. C., Ostapovicz D., Cannistra S. A. Secretion of interleukin-1 by acute myeloblastic leukemia cells in vitro induces endothelial cells to secrete colony stimulating factors. Blood. 1987 Oct;70(4):1218–1221. [PubMed] [Google Scholar]
  9. Griffin J. D., Ritz J., Nadler L. M., Schlossman S. F. Expression of myeloid differentiation antigens on normal and malignant myeloid cells. J Clin Invest. 1981 Oct;68(4):932–941. doi: 10.1172/JCI110348. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Griffin J. D., Young D., Herrmann F., Wiper D., Wagner K., Sabbath K. D. Effects of recombinant human GM-CSF on proliferation of clonogenic cells in acute myeloblastic leukemia. Blood. 1986 May;67(5):1448–1453. [PubMed] [Google Scholar]
  11. Haegeman G., Content J., Volckaert G., Derynck R., Tavernier J., Fiers W. Structural analysis of the sequence coding for an inducible 26-kDa protein in human fibroblasts. Eur J Biochem. 1986 Sep 15;159(3):625–632. doi: 10.1111/j.1432-1033.1986.tb09931.x. [DOI] [PubMed] [Google Scholar]
  12. Herrmann F., Bambach T., Bonifer R., Lindemann A., Riedel D., Oster W., Mertelsmann R. The suppressive effects of recombinant human tumor necrosis factor-alpha on normal and malignant myelopoiesis: synergism with interferon-gamma. Int J Cell Cloning. 1988 Jul;6(4):241–261. doi: 10.1002/stem.5530060403. [DOI] [PubMed] [Google Scholar]
  13. Herrmann F., Oster W., Lindemann A., Ganser A., Dörken B., Knapp W., Griffin J. D., Mertelsmann R. Leukemic colony-forming cells in acute myeloblastic leukemia: maturation hierarchy and growth conditions. Haematol Blood Transfus. 1987;31:185–190. doi: 10.1007/978-3-642-72624-8_41. [DOI] [PubMed] [Google Scholar]
  14. Hirano T., Taga T., Yasukawa K., Nakajima K., Nakano N., Takatsuki F., Shimizu M., Murashima A., Tsunasawa S., Sakiyama F. Human B-cell differentiation factor defined by an anti-peptide antibody and its possible role in autoantibody production. Proc Natl Acad Sci U S A. 1987 Jan;84(1):228–231. doi: 10.1073/pnas.84.1.228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hirano T., Yasukawa K., Harada H., Taga T., Watanabe Y., Matsuda T., Kashiwamura S., Nakajima K., Koyama K., Iwamatsu A. Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature. 1986 Nov 6;324(6092):73–76. doi: 10.1038/324073a0. [DOI] [PubMed] [Google Scholar]
  16. Hoang T., Nara N., Wong G., Clark S., Minden M. D., McCulloch E. A. Effects of recombinant GM-CSF on the blast cells of acute myeloblastic leukemia. Blood. 1986 Jul;68(1):313–316. [PubMed] [Google Scholar]
  17. Ikebuchi K., Wong G. G., Clark S. C., Ihle J. N., Hirai Y., Ogawa M. Interleukin 6 enhancement of interleukin 3-dependent proliferation of multipotential hemopoietic progenitors. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9035–9039. doi: 10.1073/pnas.84.24.9035. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Jaffe E. A., Nachman R. L., Becker C. G., Minick C. R. Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J Clin Invest. 1973 Nov;52(11):2745–2756. doi: 10.1172/JCI107470. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kawano M., Hirano T., Matsuda T., Taga T., Horii Y., Iwato K., Asaoku H., Tang B., Tanabe O., Tanaka H. Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature. 1988 Mar 3;332(6159):83–85. doi: 10.1038/332083a0. [DOI] [PubMed] [Google Scholar]
  20. Kelleher C., Miyauchi J., Wong G., Clark S., Minden M. D., McCulloch E. A. Synergism between recombinant growth factors, GM-CSF and G-CSF, acting on the blast cells of acute myeloblastic leukemia. Blood. 1987 May;69(5):1498–1503. [PubMed] [Google Scholar]
  21. Kohase M., Henriksen-DeStefano D., May L. T., Vilcek J., Sehgal P. B. Induction of beta 2-interferon by tumor necrosis factor: a homeostatic mechanism in the control of cell proliferation. Cell. 1986 Jun 6;45(5):659–666. doi: 10.1016/0092-8674(86)90780-4. [DOI] [PubMed] [Google Scholar]
  22. Kohase M., May L. T., Tamm I., Vilcek J., Sehgal P. B. A cytokine network in human diploid fibroblasts: interactions of beta-interferons, tumor necrosis factor, platelet-derived growth factor, and interleukin-1. Mol Cell Biol. 1987 Jan;7(1):273–280. doi: 10.1128/mcb.7.1.273. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Leary A. G., Ikebuchi K., Hirai Y., Wong G. G., Yang Y. C., Clark S. C., Ogawa M. Synergism between interleukin-6 and interleukin-3 in supporting proliferation of human hematopoietic stem cells: comparison with interleukin-1 alpha. Blood. 1988 Jun;71(6):1759–1763. [PubMed] [Google Scholar]
  24. May L. T., Helfgott D. C., Sehgal P. B. Anti-beta-interferon antibodies inhibit the increased expression of HLA-B7 mRNA in tumor necrosis factor-treated human fibroblasts: structural studies of the beta 2 interferon involved. Proc Natl Acad Sci U S A. 1986 Dec;83(23):8957–8961. doi: 10.1073/pnas.83.23.8957. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Miyauchi J., Kelleher C. A., Yang Y. C., Wong G. G., Clark S. C., Minden M. D., Minkin S., McCulloch E. A. The effects of three recombinant growth factors, IL-3, GM-CSF, and G-CSF, on the blast cells of acute myeloblastic leukemia maintained in short-term suspension culture. Blood. 1987 Sep;70(3):657–663. [PubMed] [Google Scholar]
  26. Munker R., Koeffler P. In vitro action of tumor necrosis factor on myeloid leukemia cells. Blood. 1987 Apr;69(4):1102–1108. [PubMed] [Google Scholar]
  27. Oster W., Lindemann A., Horn S., Mertelsmann R., Herrmann F. Tumor necrosis factor (TNF)-alpha but not TNF-beta induces secretion of colony stimulating factor for macrophages (CSF-1) by human monocytes. Blood. 1987 Nov;70(5):1700–1703. [PubMed] [Google Scholar]
  28. Oster W., Lindemann A., Mertelsmann R., Herrmann F. Regulation of gene expression of M-, G-, GM-, and multi-CSF in normal and malignant hematopoietic cells. Blood Cells. 1988;14(2-3):443–462. [PubMed] [Google Scholar]
  29. Pike B. L., Robinson W. A. Human bone marrow colony growth in agar-gel. J Cell Physiol. 1970 Aug;76(1):77–84. doi: 10.1002/jcp.1040760111. [DOI] [PubMed] [Google Scholar]
  30. Souza L. M., Boone T. C., Gabrilove J., Lai P. H., Zsebo K. M., Murdock D. C., Chazin V. R., Bruszewski J., Lu H., Chen K. K. Recombinant human granulocyte colony-stimulating factor: effects on normal and leukemic myeloid cells. Science. 1986 Apr 4;232(4746):61–65. doi: 10.1126/science.2420009. [DOI] [PubMed] [Google Scholar]
  31. Tosato G., Seamon K. B., Goldman N. D., Sehgal P. B., May L. T., Washington G. C., Jones K. D., Pike S. E. Monocyte-derived human B-cell growth factor identified as interferon-beta 2 (BSF-2, IL-6). Science. 1988 Jan 29;239(4839):502–504. doi: 10.1126/science.2829354. [DOI] [PubMed] [Google Scholar]
  32. Van Damme J., De Ley M., Opdenakker G., Billiau A., De Somer P., Van Beeumen J. Homogeneous interferon-inducing 22K factor is related to endogenous pyrogen and interleukin-1. Nature. 1985 Mar 21;314(6008):266–268. doi: 10.1038/314266a0. [DOI] [PubMed] [Google Scholar]
  33. Van Damme J., Opdenakker G., Simpson R. J., Rubira M. R., Cayphas S., Vink A., Billiau A., Van Snick J. Identification of the human 26-kD protein, interferon beta 2 (IFN-beta 2), as a B cell hybridoma/plasmacytoma growth factor induced by interleukin 1 and tumor necrosis factor. J Exp Med. 1987 Mar 1;165(3):914–919. doi: 10.1084/jem.165.3.914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Vaquero C., Sanceau J., Weissenbach J., Beranger F., Falcoff R. Regulation of human gamma-interferon and beta-interferon gene expression in PHA-activated lymphocytes. J Interferon Res. 1986 Apr;6(2):161–170. doi: 10.1089/jir.1986.6.161. [DOI] [PubMed] [Google Scholar]
  35. Vellenga E., Young D. C., Wagner K., Wiper D., Ostapovicz D., Griffin J. D. The effects of GM-CSF and G-CSF in promoting growth of clonogenic cells in acute myeloblastic leukemia. Blood. 1987 Jun;69(6):1771–1776. [PubMed] [Google Scholar]
  36. Wong G. H., Goeddel D. V. Tumour necrosis factors alpha and beta inhibit virus replication and synergize with interferons. 1986 Oct 30-Nov 5Nature. 323(6091):819–822. doi: 10.1038/323819a0. [DOI] [PubMed] [Google Scholar]
  37. Yasukawa K., Hirano T., Watanabe Y., Muratani K., Matsuda T., Nakai S., Kishimoto T. Structure and expression of human B cell stimulatory factor-2 (BSF-2/IL-6) gene. EMBO J. 1987 Oct;6(10):2939–2945. doi: 10.1002/j.1460-2075.1987.tb02598.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Young D. C., Wagner K., Griffin J. D. Constitutive expression of the granulocyte-macrophage colony-stimulating factor gene in acute myeloblastic leukemia. J Clin Invest. 1987 Jan;79(1):100–106. doi: 10.1172/JCI112769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Zilberstein A., Ruggieri R., Korn J. H., Revel M. Structure and expression of cDNA and genes for human interferon-beta-2, a distinct species inducible by growth-stimulatory cytokines. EMBO J. 1986 Oct;5(10):2529–2537. doi: 10.1002/j.1460-2075.1986.tb04531.x. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES