Abstract
Interleukin (IL)-6 is known to be an essential growth factor for myeloma cells, both in vitro and in vivo. In mice, IL-6 is required for development of B cell tumors upon infection with a retrovirus expressing the myc/raf oncogenes. In the present study, we used the pristane-oil-induced plasmacytoma model, which more closely mimics tumor transformation and progression in human multiple myeloma. Also using this system, we found that IL-6-deficient BALB/c mice are protected against tumor development. Although the pristane-induced inflammatory reaction was less pronounced in IL-6-deficient mice versus their wild-type littermates, both B cell differentiation and plasma cell formation took place, and even morphological evidence of plasma cell transformation was detected, albeit at a low frequency. However, in the absence of IL-6, there were never signs of uncontrolled proliferation of either normal B lymphocytes or tumor cells, suggesting that the role of IL-6 in murine plasmacytoma and possibly also in human multiple myeloma is to ensure abnormal survival and proliferation of previously transformed tumor cells and therefore tumor development and progression.
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Selected References
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- Bataille R., Barlogie B., Lu Z. Y., Rossi J. F., Lavabre-Bertrand T., Beck T., Wijdenes J., Brochier J., Klein B. Biologic effects of anti-interleukin-6 murine monoclonal antibody in advanced multiple myeloma. Blood. 1995 Jul 15;86(2):685–691. [PubMed] [Google Scholar]
- 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]
- Dedera D. A., Urashima M., Chauhan D., LeBrun D. P., Bronson R. T., Anderson K. C. Interleukin-6 is required for pristane-induced plasma cell hyperplasia in mice. Br J Haematol. 1996 Jul;94(1):53–61. doi: 10.1046/j.1365-2141.1996.6282074.x. [DOI] [PubMed] [Google Scholar]
- Degrassi A., Hilbert D. M., Rudikoff S., Anderson A. O., Potter M., Coon H. G. In vitro culture of primary plasmacytomas requires stromal cell feeder layers. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):2060–2064. doi: 10.1073/pnas.90.5.2060. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Demartis A., Bernassola F., Savino R., Melino G., Ciliberto G. Interleukin 6 receptor superantagonists are potent inducers of human multiple myeloma cell death. Cancer Res. 1996 Sep 15;56(18):4213–4218. [PubMed] [Google Scholar]
- Fattori E., Cappelletti M., Costa P., Sellitto C., Cantoni L., Carelli M., Faggioni R., Fantuzzi G., Ghezzi P., Poli V. Defective inflammatory response in interleukin 6-deficient mice. J Exp Med. 1994 Oct 1;180(4):1243–1250. doi: 10.1084/jem.180.4.1243. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hardin J., MacLeod S., Grigorieva I., Chang R., Barlogie B., Xiao H., Epstein J. Interleukin-6 prevents dexamethasone-induced myeloma cell death. Blood. 1994 Nov 1;84(9):3063–3070. [PubMed] [Google Scholar]
- Hilbert D. M., Kopf M., Mock B. A., Köhler G., Rudikoff S. Interleukin 6 is essential for in vivo development of B lineage neoplasms. J Exp Med. 1995 Jul 1;182(1):243–248. doi: 10.1084/jem.182.1.243. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hilbert D. M., Migone T. S., Kopf M., Leonard W. J., Rudikoff S. Distinct tumorigenic potential of abl and raf in B cell neoplasia: abl activates the IL-6 signaling pathway. Immunity. 1996 Jul;5(1):81–89. doi: 10.1016/s1074-7613(00)80312-x. [DOI] [PubMed] [Google Scholar]
- Hilbert D. M., Shen M. Y., Rapp U. R., Rudikoff S. T cells induce terminal differentiation of transformed B cells to mature plasma cell tumors. Proc Natl Acad Sci U S A. 1995 Jan 31;92(3):649–653. doi: 10.1073/pnas.92.3.649. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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]
- Kawano M. M., Mihara K., Huang N., Tsujimoto T., Kuramoto A. Differentiation of early plasma cells on bone marrow stromal cells requires interleukin-6 for escaping from apoptosis. Blood. 1995 Jan 15;85(2):487–494. [PubMed] [Google Scholar]
- 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]
- Kishimoto T., Hirano T. Molecular regulation of B lymphocyte response. Annu Rev Immunol. 1988;6:485–512. doi: 10.1146/annurev.iy.06.040188.002413. [DOI] [PubMed] [Google Scholar]
- Klein B. Cytokine, cytokine receptors, transduction signals, and oncogenes in human multiple myeloma. Semin Hematol. 1995 Jan;32(1):4–19. [PubMed] [Google Scholar]
- 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]
- 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]
- Klein B., Zhang X. G., Lu Z. Y., Bataille R. Interleukin-6 in human multiple myeloma. Blood. 1995 Feb 15;85(4):863–872. [PubMed] [Google Scholar]
- Lu Z. Y., Zhang X. G., Rodriguez C., Wijdenes J., Gu Z. J., Morel-Fournier B., Harousseau J. L., Bataille R., Rossi J. F., Klein B. Interleukin-10 is a proliferation factor but not a differentiation factor for human myeloma cells. Blood. 1995 May 1;85(9):2521–2527. [PubMed] [Google Scholar]
- Nachbaur D. M., Herold M., Maneschg A., Huber H. Serum levels of interleukin-6 in multiple myeloma and other hematological disorders: correlation with disease activity and other prognostic parameters. Ann Hematol. 1991 Feb-Mar;62(2-3):54–58. doi: 10.1007/BF01714900. [DOI] [PubMed] [Google Scholar]
- Nordan R. P., Potter M. A macrophage-derived factor required by plasmacytomas for survival and proliferation in vitro. Science. 1986 Aug 1;233(4763):566–569. doi: 10.1126/science.3726549. [DOI] [PubMed] [Google Scholar]
- Poli V., Balena R., Fattori E., Markatos A., Yamamoto M., Tanaka H., Ciliberto G., Rodan G. A., Costantini F. Interleukin-6 deficient mice are protected from bone loss caused by estrogen depletion. EMBO J. 1994 Mar 1;13(5):1189–1196. doi: 10.1002/j.1460-2075.1994.tb06368.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Potter M., Wax J. S. Peritoneal plasmacytomagenesis in mice: comparison of different pristane dose regimens. J Natl Cancer Inst. 1983 Aug;71(2):391–395. [PubMed] [Google Scholar]
- Potter M., Wiener F. Plasmacytomagenesis in mice: model of neoplastic development dependent upon chromosomal translocations. Carcinogenesis. 1992 Oct;13(10):1681–1697. doi: 10.1093/carcin/13.10.1681. [DOI] [PubMed] [Google Scholar]
- Reibnegger G., Krainer M., Herold M., Ludwig H., Wachter H., Huber H. Predictive value of interleukin-6 and neopterin in patients with multiple myeloma. Cancer Res. 1991 Dec 1;51(23 Pt 1):6250–6253. [PubMed] [Google Scholar]
- Romano M., Sironi M., Toniatti C., Polentarutti N., Fruscella P., Ghezzi P., Faggioni R., Luini W., van Hinsbergh V., Sozzani S. Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity. 1997 Mar;6(3):315–325. doi: 10.1016/s1074-7613(00)80334-9. [DOI] [PubMed] [Google Scholar]
- Schwarze M. M., Hawley R. G. Prevention of myeloma cell apoptosis by ectopic bcl-2 expression or interleukin 6-mediated up-regulation of bcl-xL. Cancer Res. 1995 Jun 1;55(11):2262–2265. [PubMed] [Google Scholar]
- Suematsu S., Matsusaka T., Matsuda T., Ohno S., Miyazaki J., Yamamura K., Hirano T., Kishimoto T. Generation of plasmacytomas with the chromosomal translocation t(12;15) in interleukin 6 transgenic mice. Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):232–235. doi: 10.1073/pnas.89.1.232. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Van Snick J., Vink A., Cayphas S., Uyttenhove C. Interleukin-HP1, a T cell-derived hybridoma growth factor that supports the in vitro growth of murine plasmacytomas. J Exp Med. 1987 Mar 1;165(3):641–649. doi: 10.1084/jem.165.3.641. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Zhang X. G., Gaillard J. P., Robillard N., Lu Z. Y., Gu Z. J., Jourdan M., Boiron J. M., Bataille R., Klein B. Reproducible obtaining of human myeloma cell lines as a model for tumor stem cell study in human multiple myeloma. Blood. 1994 Jun 15;83(12):3654–3663. [PubMed] [Google Scholar]
- Zhang X. G., Gu J. J., Lu Z. Y., Yasukawa K., Yancopoulos G. D., Turner K., Shoyab M., Taga T., Kishimoto T., Bataille R. 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. J Exp Med. 1994 Apr 1;179(4):1337–1342. doi: 10.1084/jem.179.4.1337. [DOI] [PMC free article] [PubMed] [Google Scholar]