Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1994 Apr 1;179(4):1337–1342. doi: 10.1084/jem.179.4.1337

Ciliary neurotropic factor, interleukin 11, leukemia inhibitory factor, and oncostatin M are growth factors for human myeloma cell lines using the interleukin 6 signal transducer gp130

PMCID: PMC2191454  PMID: 8145045

Abstract

Interleukin 6 (IL-6) is a major growth factor for tumor plasma cells involved in human multiple myeloma (MM). In particular, human myeloma cell lines (HMCL), whose growth is completely dependent on addition of exogenous IL-6, can be obtained reproducibly from every patient with terminal disease. Four cytokines, ciliary neurotropic factor (CNTF), IL- 11, leukemia inhibitory factor (LIF), and oncostatin M (OM), use the same transducer chain (signal transducer gp130) as IL-6 and share numerous biological activities with this IL. We found that these four cytokines stimulated proliferation and supported the long-term growth of two out of four IL-6-dependent HMCL obtained in our laboratory. Half- maximal proliferation was obtained with cytokine concentrations ranging from 0.4 to 1.2 ng/ml for IL-11, LIF, and OM. CNTF worked at high concentrations only (90 ng/ml), but addition of soluble CNTF receptor increased sensitivity to CNTF 30-fold. The growth-promoting effect of these four cytokines was abrogated by anti-gp130 antibodies, contrary to results for anti-IL-6 receptor or anti-IL-6 antibodies. No detectable changes in the morphology and phenotype were found when myeloma cells were cultured with one of these four cytokines instead of IL-6. Concordant with their IL-6-dependent growth, the four HMCL expressed membrane IL-6R and gp130 detected by FACS analysis. LIF- binding chain gene (LIFR) was expressed only in the two HMCL responsive to LIF and OM.

Full Text

The Full Text of this article is available as a PDF (589.3 KB).

Selected References

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

  1. 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]
  2. Davis S., Aldrich T. H., Ip N. Y., Stahl N., Scherer S., Farruggella T., DiStefano P. S., Curtis R., Panayotatos N., Gascan H. Released form of CNTF receptor alpha component as a soluble mediator of CNTF responses. Science. 1993 Mar 19;259(5102):1736–1739. doi: 10.1126/science.7681218. [DOI] [PubMed] [Google Scholar]
  3. Davis S., Aldrich T. H., Stahl N., Pan L., Taga T., Kishimoto T., Ip N. Y., Yancopoulos G. D. LIFR beta and gp130 as heterodimerizing signal transducers of the tripartite CNTF receptor. Science. 1993 Jun 18;260(5115):1805–1808. doi: 10.1126/science.8390097. [DOI] [PubMed] [Google Scholar]
  4. Davis S., Aldrich T. H., Valenzuela D. M., Wong V. V., Furth M. E., Squinto S. P., Yancopoulos G. D. The receptor for ciliary neurotrophic factor. Science. 1991 Jul 5;253(5015):59–63. doi: 10.1126/science.1648265. [DOI] [PubMed] [Google Scholar]
  5. Gaillard J. P., Bataille R., Brailly H., Zuber C., Yasukawa K., Attal M., Maruo N., Taga T., Kishimoto T., Klein B. Increased and highly stable levels of functional soluble interleukin-6 receptor in sera of patients with monoclonal gammopathy. Eur J Immunol. 1993 Apr;23(4):820–824. doi: 10.1002/eji.1830230408. [DOI] [PubMed] [Google Scholar]
  6. Gearing D. P., Comeau M. R., Friend D. J., Gimpel S. D., Thut C. J., McGourty J., Brasher K. K., King J. A., Gillis S., Mosley B. The IL-6 signal transducer, gp130: an oncostatin M receptor and affinity converter for the LIF receptor. Science. 1992 Mar 13;255(5050):1434–1437. doi: 10.1126/science.1542794. [DOI] [PubMed] [Google Scholar]
  7. Gearing D. P., Thut C. J., VandeBos T., Gimpel S. D., Delaney P. B., King J., Price V., Cosman D., Beckmann M. P. Leukemia inhibitory factor receptor is structurally related to the IL-6 signal transducer, gp130. EMBO J. 1991 Oct;10(10):2839–2848. doi: 10.1002/j.1460-2075.1991.tb07833.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Hirano T., Akira S., Taga T., Kishimoto T. Biological and clinical aspects of interleukin 6. Immunol Today. 1990 Dec;11(12):443–449. doi: 10.1016/0167-5699(90)90173-7. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. Ip N. Y., Nye S. H., Boulton T. G., Davis S., Taga T., Li Y., Birren S. J., Yasukawa K., Kishimoto T., Anderson D. J. CNTF and LIF act on neuronal cells via shared signaling pathways that involve the IL-6 signal transducing receptor component gp130. Cell. 1992 Jun 26;69(7):1121–1132. doi: 10.1016/0092-8674(92)90634-o. [DOI] [PubMed] [Google Scholar]
  11. Jourdan M., Zhang X. G., Portier M., Boiron J. M., Bataille R., Klein B. IFN-alpha induces autocrine production of IL-6 in myeloma cell lines. J Immunol. 1991 Dec 15;147(12):4402–4407. [PubMed] [Google Scholar]
  12. Klein B., Bataille R. Cytokine network in human multiple myeloma. Hematol Oncol Clin North Am. 1992 Apr;6(2):273–284. [PubMed] [Google Scholar]
  13. Klein B., Wijdenes J., Zhang X. G., Jourdan M., Boiron J. M., Brochier J., Liautard J., Merlin M., Clement C., Morel-Fournier B. Murine anti-interleukin-6 monoclonal antibody therapy for a patient with plasma cell leukemia. Blood. 1991 Sep 1;78(5):1198–1204. [PubMed] [Google Scholar]
  14. Klein B., Zhang X. G., Jourdan M., Boiron J. M., Portier M., Lu Z. Y., Wijdenes J., Brochier J., Bataille R. Interleukin-6 is the central tumor growth factor in vitro and in vivo in multiple myeloma. Eur Cytokine Netw. 1990 Oct-Nov;1(4):193–201. [PubMed] [Google Scholar]
  15. Layton M. J., Cross B. A., Metcalf D., Ward L. D., Simpson R. J., Nicola N. A. A major binding protein for leukemia inhibitory factor in normal mouse serum: identification as a soluble form of the cellular receptor. Proc Natl Acad Sci U S A. 1992 Sep 15;89(18):8616–8620. doi: 10.1073/pnas.89.18.8616. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Liu J., Modrell B., Aruffo A., Marken J. S., Taga T., Yasukawa K., Murakami M., Kishimoto T., Shoyab M. Interleukin-6 signal transducer gp130 mediates oncostatin M signaling. J Biol Chem. 1992 Aug 25;267(24):16763–16766. [PubMed] [Google Scholar]
  17. Miles S. A., Martínez-Maza O., Rezai A., Magpantay L., Kishimoto T., Nakamura S., Radka S. F., Linsley P. S. Oncostatin M as a potent mitogen for AIDS-Kaposi's sarcoma-derived cells. Science. 1992 Mar 13;255(5050):1432–1434. doi: 10.1126/science.1542793. [DOI] [PubMed] [Google Scholar]
  18. Narazaki M., Yasukawa K., Saito T., Ohsugi Y., Fukui H., Koishihara Y., Yancopoulos G. D., Taga T., Kishimoto T. Soluble forms of the interleukin-6 signal-transducing receptor component gp130 in human serum possessing a potential to inhibit signals through membrane-anchored gp130. Blood. 1993 Aug 15;82(4):1120–1126. [PubMed] [Google Scholar]
  19. Saito T., Taga T., Miki D., Futatsugi K., Yawata H., Kishimoto T., Yasukawa K. Preparation of monoclonal antibodies against the IL-6 signal transducer, gp130, that can inhibit IL-6-mediated functions. J Immunol Methods. 1993 Aug 9;163(2):217–223. doi: 10.1016/0022-1759(93)90125-q. [DOI] [PubMed] [Google Scholar]
  20. Scutt A., Mayer H., Wingender E. New perspectives in the differentiation of bone-forming cells. Biofactors. 1992 Dec;4(1):1–13. [PubMed] [Google Scholar]
  21. Taga T., Hibi M., Hirata Y., Yamasaki K., Yasukawa K., Matsuda T., Hirano T., Kishimoto T. Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell. 1989 Aug 11;58(3):573–581. doi: 10.1016/0092-8674(89)90438-8. [DOI] [PubMed] [Google Scholar]
  22. Taga T., Narazaki M., Yasukawa K., Saito T., Miki D., Hamaguchi M., Davis S., Shoyab M., Yancopoulos G. D., Kishimoto T. Functional inhibition of hematopoietic and neurotrophic cytokines by blocking the interleukin 6 signal transducer gp130. Proc Natl Acad Sci U S A. 1992 Nov 15;89(22):10998–11001. doi: 10.1073/pnas.89.22.10998. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. 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]
  24. Yasukawa K., Futatsugi K., Saito T., Yawata H., Narazaki M., Suzuki H., Taga T., Kishimoto T. Association of recombinant soluble IL-6-signal transducer, gp130, with a complex of IL 6 and soluble IL-6 receptor, and establishment of an ELISA for soluble gp130. Immunol Lett. 1992 Feb;31(2):123–130. doi: 10.1016/0165-2478(92)90138-e. [DOI] [PubMed] [Google Scholar]
  25. Yin T., Taga T., Tsang M. L., Yasukawa K., Kishimoto T., Yang Y. C. Involvement of IL-6 signal transducer gp130 in IL-11-mediated signal transduction. J Immunol. 1993 Sep 1;151(5):2555–2561. [PubMed] [Google Scholar]

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

RESOURCES