Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1990 Jul 1;172(1):61–68. doi: 10.1084/jem.172.1.61

Expression of an exogenous interleukin 6 gene in human Epstein Barr virus B cells confers growth advantage and in vivo tumorigenicity

PMCID: PMC2188154  PMID: 2162905

Abstract

The biological role of interleukin 6 (IL-6) molecules in human B cell tumorigenesis was studied by using an episomal expression vector, pHEBoSV-IL6, to introduce stably the human IL-6 gene into human Epstein Barr virus (EBV)-transformed B lymphoblasts. The gene was present in the IL-6-transfected cells in a high copy number and was efficiently expressed, resulting in the secretion of consistent levels of IL-6 molecules. The constitutive expression of the IL-6 gene led to an altered pattern of growth and to a malignant phenotype, as shown by clonogenicity in to an altered pattern of growth and to a malignant phenotype, as shown by clonogenicity in soft agar cultures and tumorigenicity in nude mice. These data suggest that the combined action of EBV, which exerts an immortalizing function, and of the growth-promoting activity of IL-6 molecules, can give rise to fully transformed B cell tumors in immunodeficient subjects.

Full Text

The Full Text of this article is available as a PDF (1,023.9 KB).

Selected References

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

  1. Arione R., Jemma C., Forni M., Marchese C., Benetton G., Giubellino C., Modesti A., Martinotti M. G., di Montezemolo L. C., Musso T. A new childhood T-cell lymphoma established in nude mice and in vitro. Cancer Res. 1988 Mar 1;48(5):1312–1318. [PubMed] [Google Scholar]
  2. Blair D. G., Cooper C. S., Oskarsson M. K., Eader L. A., Vande Woude G. F. New method for detecting cellular transforming genes. Science. 1982 Dec 10;218(4577):1122–1125. doi: 10.1126/science.6293052. [DOI] [PubMed] [Google Scholar]
  3. 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]
  4. Gootenberg J. E., Ruscetti F. W., Mier J. W., Gazdar A., Gallo R. C. Human cutaneous T cell lymphoma and leukemia cell lines produce and respond to T cell growth factor. J Exp Med. 1981 Nov 1;154(5):1403–1418. doi: 10.1084/jem.154.5.1403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Gordon J., Ley S. C., Melamed M. D., Aman P., Hughes-Jones N. C. Soluble factor requirements for the autostimulatory growth of B lymphoblasts immortalized by Epstein-Barr virus. J Exp Med. 1984 May 1;159(5):1554–1559. doi: 10.1084/jem.159.5.1554. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Hirt B. Selective extraction of polyoma DNA from infected mouse cell cultures. J Mol Biol. 1967 Jun 14;26(2):365–369. doi: 10.1016/0022-2836(67)90307-5. [DOI] [PubMed] [Google Scholar]
  7. Kishimoto T. The biology of interleukin-6. Blood. 1989 Jul;74(1):1–10. [PubMed] [Google Scholar]
  8. Lombardi L., Newcomb E. W., Dalla-Favera R. Pathogenesis of Burkitt lymphoma: expression of an activated c-myc oncogene causes the tumorigenic conversion of EBV-infected human B lymphoblasts. Cell. 1987 Apr 24;49(2):161–170. doi: 10.1016/0092-8674(87)90556-3. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. Muraguchi A., Hirano T., Tang B., Matsuda T., Horii Y., Nakajima K., Kishimoto T. The essential role of B cell stimulatory factor 2 (BSF-2/IL-6) for the terminal differentiation of B cells. J Exp Med. 1988 Feb 1;167(2):332–344. doi: 10.1084/jem.167.2.332. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Pelicci P. G., Knowles D. M., 2nd, Arlin Z. A., Wieczorek R., Luciw P., Dina D., Basilico C., Dalla-Favera R. Multiple monoclonal B cell expansions and c-myc oncogene rearrangements in acquired immune deficiency syndrome-related lymphoproliferative disorders. Implications for lymphomagenesis. J Exp Med. 1986 Dec 1;164(6):2049–2060. doi: 10.1084/jem.164.6.2049. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Scala G., Kuang Y. D., Hall R. E., Muchmore A. V., Oppenheim J. J. Accessory cell function of human B cells. I. Production of both interleukin 1-like activity and an interleukin 1 inhibitory factor by an EBV-transformed human B cell line. J Exp Med. 1984 Jun 1;159(6):1637–1652. doi: 10.1084/jem.159.6.1637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Scala G., Morrone G., Tamburrini M., Alfinito F., Pastore C. I., D'Alessio G., Venuta S. Autocrine growth function of human interleukin 1 molecules on ROHA-9, an EBV-transformed human B cell line. J Immunol. 1987 Apr 15;138(8):2527–2534. [PubMed] [Google Scholar]
  14. Sporn M. B., Todaro G. J. Autocrine secretion and malignant transformation of cells. N Engl J Med. 1980 Oct 9;303(15):878–880. doi: 10.1056/NEJM198010093031511. [DOI] [PubMed] [Google Scholar]
  15. Suematsu S., Matsuda T., Aozasa K., Akira S., Nakano N., Ohno S., Miyazaki J., Yamamura K., Hirano T., Kishimoto T. IgG1 plasmacytosis in interleukin 6 transgenic mice. Proc Natl Acad Sci U S A. 1989 Oct;86(19):7547–7551. doi: 10.1073/pnas.86.19.7547. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Sugden B., Marsh K., Yates J. A vector that replicates as a plasmid and can be efficiently selected in B-lymphoblasts transformed by Epstein-Barr virus. Mol Cell Biol. 1985 Feb;5(2):410–413. doi: 10.1128/mcb.5.2.410. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Toneguzzo F., Hayday A. C., Keating A. Electric field-mediated DNA transfer: transient and stable gene expression in human and mouse lymphoid cells. Mol Cell Biol. 1986 Feb;6(2):703–706. doi: 10.1128/mcb.6.2.703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. 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]
  19. Van Damme J., De Ley M., Van Snick J., Dinarello C. A., Billiau A. The role of interferon-beta 1 and the 26-kDa protein (interferon-beta 2) as mediators of the antiviral effect of interleukin 1 and tumor necrosis factor. J Immunol. 1987 Sep 15;139(6):1867–1872. [PubMed] [Google Scholar]
  20. 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]
  21. Van Snick J., Cayphas S., Vink A., Uyttenhove C., Coulie P. G., Rubira M. R., Simpson R. J. Purification and NH2-terminal amino acid sequence of a T-cell-derived lymphokine with growth factor activity for B-cell hybridomas. Proc Natl Acad Sci U S A. 1986 Dec;83(24):9679–9683. doi: 10.1073/pnas.83.24.9679. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES