Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1993 Nov;92(5):2346–2352. doi: 10.1172/JCI116839

Interleukin-6 functions as an intracellular growth factor in hairy cell leukemia in vitro.

B Barut 1, D Chauhan 1, H Uchiyama 1, K C Anderson 1
PMCID: PMC288416  PMID: 8227350

Abstract

The role of interleukin-6 (IL-6) in the growth of B cell derived hairy cell leukemia (HCL) was characterized. Purified hairy cells (HCs) did not increase DNA synthesis in vitro in response to exogenous IL-6; however, they expressed IL-6 receptor (IL-6R) mRNA and bound directly fluorochrome labeled IL-6. IL-6 mRNA was not detectable in tumor cells by Northern blotting, but was evident using PCR amplification. Although intracytoplasmic IL-6 protein was not demonstrable, HCs did secrete low levels of IL-6. Neutralizing antibody to IL-6 did not inhibit HC DNA synthesis. Since tumor necrosis factor (TNF) is a growth factor for HCL, we determined whether the TNF effect could be IL-6-mediated. TNF markedly augmented in vitro DNA synthesis by HCs. TNF did not alter IL-6R expression or IL-6 binding; however, IL-6 mRNA and IL-6 protein were detectable after 3-d culture of HCs with TNF. In addition, IL-6 secretion by HCs was markedly augmented by TNF. Finally, although neither IL-6 nor anti-IL-6 antibody altered TNF-induced DNA synthesis by HCs, IL-6 antisense oligonucleotide inhibited TNF-induced DNA synthesis and IL-6 secretion by HCs. Therefore, IL-6 does not directly affect the growth of HCL, but rather mediates TNF-induced DNA synthesis via an intracytoplasmic mechanism.

Full text

PDF
2350

Images in this article

2349Image
on p.2349
2349Image
on p.2349
2349Image
on p.2349
2350Image
on p.2350
2350Image
on p.2350

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. Anderson K. C., Boyd A. W., Fisher D. C., Leslie D., Schlossman S. F., Nadler L. M. Hairy cell leukemia: a tumor of pre-plasma cells. Blood. 1985 Mar;65(3):620–629. [PubMed] [Google Scholar]
  3. Anderson K. C., Jones R. M., Morimoto C., Leavitt P., Barut B. A. Response patterns of purified myeloma cells to hematopoietic growth factors. Blood. 1989 May 15;73(7):1915–1924. [PubMed] [Google Scholar]
  4. Anderson K. C., Park E. K., Bates M. P., Leonard R. C., Hardy R., Schlossman S. F., Nadler L. M. Antigens on human plasma cells identified by monoclonal antibodies. J Immunol. 1983 Mar;130(3):1132–1138. [PubMed] [Google Scholar]
  5. Barut B. A., Cochran M. K., O'Hara C., Anderson K. C. Response patterns of hairy cell leukemia to B-cell mitogens and growth factors. Blood. 1990 Nov 15;76(10):2091–2097. [PubMed] [Google Scholar]
  6. Bataille R., Jourdan M., Zhang X. G., Klein B. Serum levels of interleukin 6, a potent myeloma cell growth factor, as a reflect of disease severity in plasma cell dyscrasias. J Clin Invest. 1989 Dec;84(6):2008–2011. doi: 10.1172/JCI114392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bejcek B. E., Li D. Y., Deuel T. F. Transformation by v-sis occurs by an internal autoactivation mechanism. Science. 1989 Sep 29;245(4925):1496–1499. doi: 10.1126/science.2551043. [DOI] [PubMed] [Google Scholar]
  8. Bergamaschi G., Cazzola M., Rosti V., Carlo-Stella C., Santini V., Ponchio L., Peverali F. A., Della Valle G., Rossi Ferrini P., Ascari E. Tumor necrosis factor alpha modulates the messenger RNA expression of hematopoietic growth factor genes in fresh blast cells from patients with acute myeloblastic leukemia. Leukemia. 1991 Oct;5(10):886–891. [PubMed] [Google Scholar]
  9. Billard C., Sigaux F., Wietzerbin J. IFN-alpha in vivo enhances tumor necrosis factor receptor levels on hairy cells. J Immunol. 1990 Sep 15;145(6):1713–1718. [PubMed] [Google Scholar]
  10. Biondi A., Rossi V., Bassan R., Barbui T., Bettoni S., Sironi M., Mantovani A., Rambaldi A. Constitutive expression of the interleukin-6 gene in chronic lymphocytic leukemia. Blood. 1989 Apr;73(5):1279–1284. [PubMed] [Google Scholar]
  11. Brach M. A., Cicco N. A., Riedel D., Hirano T., Kishimoto T., Mertelsmann R. H., Herrmann F. Mechanisms of differential regulation of interleukin-6 mRNA accumulation by tumor necrosis factor alpha and lymphotoxin during monocytic differentiation. FEBS Lett. 1990 Apr 24;263(2):349–354. doi: 10.1016/0014-5793(90)81411-g. [DOI] [PubMed] [Google Scholar]
  12. Browder T. M., Abrams J. S., Wong P. M., Nienhuis A. W. Mechanism of autocrine stimulation in hematopoietic cells producing interleukin-3 after retrovirus-mediated gene transfer. Mol Cell Biol. 1989 Jan;9(1):204–213. doi: 10.1128/mcb.9.1.204. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Buck C., Digel W., Schöniger W., Stefanic M., Ragnavachar A., Heimpel H., Porzsolt F. Tumor necrosis factor-alpha, but not lymphotoxin, stimulates growth of tumor cells in hairy cell leukemia. Leukemia. 1990 Jun;4(6):431–434. [PubMed] [Google Scholar]
  14. Caligaris-Cappio F., Bergui L., Gregoretti M. G., Gaidano G., Gaboli M., Schena M., Zallone A. Z., Marchisio P. C. 'Role of bone marrow stromal cells in the growth of human multiple myeloma. Blood. 1991 Jun 15;77(12):2688–2693. [PubMed] [Google Scholar]
  15. Carson D. A., Wasson D. B., Taetle R., Yu A. Specific toxicity of 2-chlorodeoxyadenosine toward resting and proliferating human lymphocytes. Blood. 1983 Oct;62(4):737–743. [PubMed] [Google Scholar]
  16. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  17. Cicco N. A., Lindemann A., Content J., Vandenbussche P., Lübbert M., Gauss J., Mertelsmann R., Herrmann F. Inducible production of interleukin-6 by human polymorphonuclear neutrophils: role of granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-alpha. Blood. 1990 May 15;75(10):2049–2052. [PubMed] [Google Scholar]
  18. Cordingley F. T., Bianchi A., Hoffbrand A. V., Reittie J. E., Heslop H. E., Vyakarnam A., Turner M., Meager A., Brenner M. K. Tumour necrosis factor as an autocrine tumour growth factor for chronic B-cell malignancies. Lancet. 1988 Apr 30;1(8592):969–971. doi: 10.1016/s0140-6736(88)91782-5. [DOI] [PubMed] [Google Scholar]
  19. Dunbar C. E., Browder T. M., Abrams J. S., Nienhuis A. W. COOH-terminal-modified interleukin-3 is retained intracellularly and stimulates autocrine growth. Science. 1989 Sep 29;245(4925):1493–1496. doi: 10.1126/science.2789432. [DOI] [PubMed] [Google Scholar]
  20. Foa R., Massaia M., Cardona S., Tos A. G., Bianchi A., Attisano C., Guarini A., di Celle P. F., Fierro M. T. Production of tumor necrosis factor-alpha by B-cell chronic lymphocytic leukemia cells: a possible regulatory role of TNF in the progression of the disease. Blood. 1990 Jul 15;76(2):393–400. [PubMed] [Google Scholar]
  21. Ford R. J., Kwok D., Quesada J., Sahasrabuddhe C. G. Production of B cell growth factor(s) by neoplastic B cells from hairy cell leukemia patients. Blood. 1986 Mar;67(3):573–577. [PubMed] [Google Scholar]
  22. Ford R. J., Yoshimura L., Morgan J., Quesada J., Montagna R., Maizel A. Growth factor-mediated tumor cell proliferation in hairy cell leukemia. J Exp Med. 1985 Sep 1;162(3):1093–1098. doi: 10.1084/jem.162.3.1093. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Fox D. A., Hussey R. E., Fitzgerald K. A., Bensussan A., Daley J. F., Schlossman S. F., Reinherz E. L. Activation of human thymocytes via the 50KD T11 sheep erythrocyte binding protein induces the expression of interleukin 2 receptors on both T3+ and T3- populations. J Immunol. 1985 Jan;134(1):330–335. [PubMed] [Google Scholar]
  24. Gamliel H., Brownstein B. H., Gurfel D., Wu S. H., Rosner M. C., Golomb H. M. B-cell growth factor-induced and alpha-interferon-inhibited proliferation of hairy cells coincides with modulation of cell surface antigens. Cancer Res. 1990 Jul 1;50(13):4111–4120. [PubMed] [Google Scholar]
  25. Genot E., Valentine M. A., Degos L., Sigaux F., Kolb J. P. Hyperphosphorylation of CD20 in hairy cells. Alteration by low molecular weight B cell growth factor and IFN-alpha. J Immunol. 1991 Feb 1;146(3):870–878. [PubMed] [Google Scholar]
  26. Ghaderi A. A., Richardson P., Cardona C., Millsum M. J., Ling N., Gillis S., Ledbetter J., Gordon J. Stimulation of B-chronic lymphocytic leukemia populations by recombinant interleukin-4 and other defined growth-promoting agents. Leukemia. 1988 Mar;2(3):165–170. [PubMed] [Google Scholar]
  27. Griffiths S. D., Cawley J. C. The effect of cytokines, including IL-1, IL-4, and IL-6, in hairy cell proliferation/differentiation. Leukemia. 1990 May;4(5):337–340. [PubMed] [Google Scholar]
  28. Heslop H. E., Bianchi A. C., Cordingley F. T., Turner M., Chandima W., De Mel C. P., Hoffbrand A. V., Brenner M. K. Effects of interferon alpha on autocrine growth factor loops in B lymphoproliferative disorders. J Exp Med. 1990 Dec 1;172(6):1729–1734. doi: 10.1084/jem.172.6.1729. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Hirano T. Interleukin 6 (IL-6) and its receptor: their role in plasma cell neoplasias. Int J Cell Cloning. 1991 May;9(3):166–184. doi: 10.1002/stem.5530090303. [DOI] [PubMed] [Google Scholar]
  30. 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]
  31. Hirata Y., Taga T., Hibi M., Nakano N., Hirano T., Kishimoto T. Characterization of IL-6 receptor expression by monoclonal and polyclonal antibodies. J Immunol. 1989 Nov 1;143(9):2900–2906. [PubMed] [Google Scholar]
  32. Hitzler J. K., Martinez-Valdez H., Bergsagel D. B., Minden M. D., Messner H. A. Role of interleukin-6 in the proliferation of human multiple myeloma cell lines OCI-My 1 to 7 established from patients with advanced stage of the disease. Blood. 1991 Oct 15;78(8):1996–2004. [PubMed] [Google Scholar]
  33. Isshiki H., Akira S., Tanabe O., Nakajima T., Shimamoto T., Hirano T., Kishimoto T. Constitutive and interleukin-1 (IL-1)-inducible factors interact with the IL-1-responsive element in the IL-6 gene. Mol Cell Biol. 1990 Jun;10(6):2757–2764. doi: 10.1128/mcb.10.6.2757. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Jackson N., Lowe J., Ball J., Bromidge E., Ling N. R., Larkins S., Griffith M. J., Franklin I. M. Two new IgA1-kappa plasma cell leukaemia cell lines (JJN-1 & JJN-2) which proliferate in response to B cell stimulatory factor 2. Clin Exp Immunol. 1989 Jan;75(1):93–99. [PMC free article] [PubMed] [Google Scholar]
  35. Janckila A. J., Li C. Y., Lam K. W., Yam L. T. The cytochemistry of tartrate-resistant acid phosphatase. Technical considerations. Am J Clin Pathol. 1978 Jul;70(1):45–55. doi: 10.1093/ajcp/70.1.45. [DOI] [PubMed] [Google Scholar]
  36. Jansen J. H., Wientjens G. J., Willemze R., Kluin-Nelemans J. C. Production of tumor necrosis factor-alpha by normal and malignant B lymphocytes in response to interferon-alpha, interferon-gamma and interleukin-4. Leukemia. 1992 Feb;6(2):116–119. [PubMed] [Google Scholar]
  37. 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]
  38. Klein B., Zhang X. G., Jourdan M., Content J., Houssiau F., Aarden L., Piechaczyk M., Bataille R. Paracrine rather than autocrine regulation of myeloma-cell growth and differentiation by interleukin-6. Blood. 1989 Feb;73(2):517–526. [PubMed] [Google Scholar]
  39. Lang R. A., Metcalf D., Gough N. M., Dunn A. R., Gonda T. J. Expression of a hemopoietic growth factor cDNA in a factor-dependent cell line results in autonomous growth and tumorigenicity. Cell. 1985 Dec;43(2 Pt 1):531–542. doi: 10.1016/0092-8674(85)90182-5. [DOI] [PubMed] [Google Scholar]
  40. Levy Y., Tsapis A., Brouet J. C. Interleukin-6 antisense oligonucleotides inhibit the growth of human myeloma cell lines. J Clin Invest. 1991 Aug;88(2):696–699. doi: 10.1172/JCI115355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Libermann T. A., Baltimore D. Activation of interleukin-6 gene expression through the NF-kappa B transcription factor. Mol Cell Biol. 1990 May;10(5):2327–2334. doi: 10.1128/mcb.10.5.2327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Lindemann A., Ludwig W. D., Oster W., Mertelsmann R., Herrmann F. High-level secretion of tumor necrosis factor-alpha contributes to hematopoietic failure in hairy cell leukemia. Blood. 1989 Mar;73(4):880–884. [PubMed] [Google Scholar]
  43. Miles S. A., Rezai A. R., Salazar-González J. F., Vander Meyden M., Stevens R. H., Logan D. M., Mitsuyasu R. T., Taga T., Hirano T., Kishimoto T. AIDS Kaposi sarcoma-derived cells produce and respond to interleukin 6. Proc Natl Acad Sci U S A. 1990 Jun;87(11):4068–4072. doi: 10.1073/pnas.87.11.4068. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Nadler L. M., Anderson K. C., Marti G., Bates M., Park E., Daley J. F., Schlossman S. F. B4, a human B lymphocyte-associated antigen expressed on normal, mitogen-activated, and malignant B lymphocytes. J Immunol. 1983 Jul;131(1):244–250. [PubMed] [Google Scholar]
  45. Nadler L. M., Stashenko P., Hardy R., van Agthoven A., Terhorst C., Schlossman S. F. Characterization of a human B cell-specific antigen (B2) distinct from B1. J Immunol. 1981 May;126(5):1941–1947. [PubMed] [Google Scholar]
  46. Oster W., Cicco N. A., Klein H., Hirano T., Kishimoto T., Lindemann A., Mertelsmann R. H., Herrmann F. 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. J Clin Invest. 1989 Aug;84(2):451–457. doi: 10.1172/JCI114186. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
  47. Paganelli K. A., Evans S. S., Han T., Ozer H. B cell growth factor-induced proliferation of hairy cell lymphocytes and inhibition by type I interferon in vitro. Blood. 1986 Apr;67(4):937–942. [PubMed] [Google Scholar]
  48. Reinherz E. L., Kung P. C., Goldstein G., Schlossman S. F. A monoclonal antibody reactive with the human cytotoxic/suppressor T cell subset previously defined by a heteroantiserum termed TH2. J Immunol. 1980 Mar;124(3):1301–1307. [PubMed] [Google Scholar]
  49. Reinherz E. L., Kung P. C., Goldstein G., Schlossman S. F. Further characterization of the human inducer T cell subset defined by monoclonal antibody. J Immunol. 1979 Dec;123(6):2894–2896. [PubMed] [Google Scholar]
  50. Rieckmann P., D'Alessandro F., Nordan R. P., Fauci A. S., Kehrl J. H. IL-6 and tumor necrosis factor-alpha. Autocrine and paracrine cytokines involved in B cell function. J Immunol. 1991 May 15;146(10):3462–3468. [PubMed] [Google Scholar]
  51. Saven A., Piro L. D. Treatment of hairy cell leukemia. Blood. 1992 Mar 1;79(5):1111–1120. [PubMed] [Google Scholar]
  52. Shimizu H., Mitomo K., Watanabe T., Okamoto S., Yamamoto K. Involvement of a NF-kappa B-like transcription factor in the activation of the interleukin-6 gene by inflammatory lymphokines. Mol Cell Biol. 1990 Feb;10(2):561–568. doi: 10.1128/mcb.10.2.561. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Shimizu S., Yoshioka R., Hirose Y., Sugai S., Tachibana J., Konda S. Establishment of two interleukin 6 (B cell stimulatory factor 2/interferon beta 2)-dependent human bone marrow-derived myeloma cell lines. J Exp Med. 1989 Jan 1;169(1):339–344. doi: 10.1084/jem.169.1.339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Stashenko P., Nadler L. M., Hardy R., Schlossman S. F. Characterization of a human B lymphocyte-specific antigen. J Immunol. 1980 Oct;125(4):1678–1685. [PubMed] [Google Scholar]
  55. Tanner J. E., Tosato G. Regulation of B-cell growth and immunoglobulin gene transcription by interleukin-6. Blood. 1992 Jan 15;79(2):452–459. [PubMed] [Google Scholar]
  56. Todd R. F., 3rd, Nadler L. M., Schlossman S. F. Antigens on human monocytes identified by monoclonal antibodies. J Immunol. 1981 Apr;126(4):1435–1442. [PubMed] [Google Scholar]
  57. Tosato G., Tanner J., Jones K. D., Revel M., Pike S. E. Identification of interleukin-6 as an autocrine growth factor for Epstein-Barr virus-immortalized B cells. J Virol. 1990 Jun;64(6):3033–3041. doi: 10.1128/jvi.64.6.3033-3041.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. 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]
  59. Vedantham S., Gamliel H., Golomb H. M. Mechanism of interferon action in hairy cell leukemia: a model of effective cancer biotherapy. Cancer Res. 1992 Mar 1;52(5):1056–1066. [PubMed] [Google Scholar]
  60. Yamasaki K., Taga T., Hirata Y., Yawata H., Kawanishi Y., Seed B., Taniguchi T., Hirano T., Kishimoto T. Cloning and expression of the human interleukin-6 (BSF-2/IFN beta 2) receptor. Science. 1988 Aug 12;241(4867):825–828. doi: 10.1126/science.3136546. [DOI] [PubMed] [Google Scholar]
  61. Yee C., Biondi A., Wang X. H., Iscove N. N., de Sousa J., Aarden L. A., Wong G. G., Clark S. C., Messner H. A., Minden M. D. A possible autocrine role for interleukin-6 in two lymphoma cell lines. Blood. 1989 Aug 1;74(2):798–804. [PubMed] [Google Scholar]
  62. Zhang X. G., Klein B., Bataille R. Interleukin-6 is a potent myeloma-cell growth factor in patients with aggressive multiple myeloma. Blood. 1989 Jul;74(1):11–13. [PubMed] [Google Scholar]
  63. Zhang Y. H., Lin J. X., Vilcek J. Interleukin-6 induction by tumor necrosis factor and interleukin-1 in human fibroblasts involves activation of a nuclear factor binding to a kappa B-like sequence. Mol Cell Biol. 1990 Jul;10(7):3818–3823. doi: 10.1128/mcb.10.7.3818. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES