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Distinct IL-6 signal transduction leads to growth arrest and death in B cells or growth promotion and cell survival in myeloma cells

Leukemia volume 16, pages 1182–1188 (2002)Cite this article

Abstract

In B cell development, interleukin-6 (IL-6) induces terminal maturation of B lymphocytes into antibody producing plasma cells. Terminal differentiated B cells cell cycle arrest and death follows. In contrast, IL-6 acts as a growth factor for malignant myeloma plasma cells and in some cases protects them from therapeutic treatment. In this study, we examined two cell lines that show different responses to IL-6. Lymphoblastoid CESS cells respond to IL-6 by terminally differentiating into antibody producing plasma cells, cell cycle arrest, and undergo cell death. Continuous addition of IL-6 to these cells induces transient activation of STAT3, SHP-2 phosphorylation, and does not alter bcl-XL and c-myc expression. In contrast, the myeloma line ANBL6 proliferates when stimulated with IL-6 and this correlates with prolonged STAT3 activation and up-regulation of bcl-XL and c-myc. Interestingly, gp130-associated SHP-2 phosphorylation was detected in the IL-6-induced CESS cells but not myeloma cell lines. The data show a very distinct IL-6 signal transduction and kinetics in these cell lines and the distinct molecular events correlate closely to the cell fate of the lymphoblast and myeloma cell lines.

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References

  1. Hirano T, Ishihara K, Hibi M . Roles of STAT3 in mediating the cell growth, differetiation and survival signals relayed through the IL-6 family of cytokine receptors Oncogene 2000 19: 2548–2556

    Article  CAS  PubMed  Google Scholar 

  2. Heinrich PC, Behrmann I, Muller-Newen G, Schaper F, Graeve L . Interleukin-6-type cytokine signaling through the gp130/Jak/STAT pathway Biochem J 1998 334: 297–314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Van Snick J . Interleukin-6: an overview Annu Rev Immunol 1990 8: 253–278

    Article  CAS  PubMed  Google Scholar 

  4. Takatsu K . Cytokines involved in B-cell differentiation and their sites of action Proc Soc Exp Biol Med 1997 215: 121–133

    Article  CAS  PubMed  Google Scholar 

  5. Chen-Kiang S . Regulation of terminal differentiation of human B-cells by IL-6 Curr Top Microbiol Immunol 1995 194: 189–198

    CAS  PubMed  Google Scholar 

  6. Benner R, Hijmans W, Haaijman JJ . The bone marrow: the major source of serum immunoglobulins, but still a neglected site of antibody formation Clin Exp Immunol 1981 46: 1–8

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Hawley RG, Berger LC . Growth control mechanisms in multiple myeloma Leuk Lymphoma 1998 29: 465–475

    Article  CAS  PubMed  Google Scholar 

  8. Rowley M, Liu P, Van Ness B . Heterogeneity in therapeutic response of genetically altered myeloma cell lines to IL-6, dexamethasone, doxorubicin, and melphalan Blood 2000 96: 3175–3180

    CAS  PubMed  Google Scholar 

  9. Cheung W-C, Van Ness B . The bone marrow stromal microenvironment influences myeloma therapeutic responses in vitro Leukemia 2001 15: 264–271

    Article  CAS  PubMed  Google Scholar 

  10. Hardin J, MacLeod S, Grigorieva I, Chang R, Barlogie B, Xiao H, Epstein J . Interleukin-6 prevents dexamethasone-induced myeloma cell death Blood 1994 84: 3063–3070

    CAS  PubMed  Google Scholar 

  11. Grigorieva I, Thomas X, Epstein J . The bone marrow stromal environment is a major factor in myeloma cell resistance to dexamethasone Exp Hematol 1998 26: 597–603

    CAS  PubMed  Google Scholar 

  12. Hirano T, Nakajima K, Hibi M . Signaling mechanisms through gp130: a model of the cytokine system Cytokine Growth Factor Rev 1997 8: 241–252

    Article  CAS  PubMed  Google Scholar 

  13. Bowman T, Garcia R, Turkson J, Jove R . STATs in oncogenesis Oncogene 2000 19: 2474–2488

    Article  CAS  PubMed  Google Scholar 

  14. Catlett-Falcone R, Landowski TH, Oshiro MM, Turkson J, Levitzki A, Savino R, Ciliberto G, Moscinski L, Fernandez-Luna JL, Nunez G, Dalton WS, Jove R . Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells Immunity 1999 10: 105–115

    Article  CAS  PubMed  Google Scholar 

  15. Rawat R, Rainey GJ, Thompson CD, Frazier-Jessen MR, Brown RT, Nordan RP . Constitutive activation of STAT3 is associated with the acquisition of an interleukin 6-independent phenotype by murine and hybridomas Blood 2000 96: 3514–3521

    CAS  PubMed  Google Scholar 

  16. Kaplan DR . Studying signal transduction in neuronal cells: the Trk/NGF system Prog Brain Res 1998 117: 35–46

    Article  CAS  PubMed  Google Scholar 

  17. Ward AC, Touw I, Yoshimura A . The Jak-Stat pathway in normal and perturbed hematopoiesis Blood 2000 95: 19–29

    CAS  PubMed  Google Scholar 

  18. Dittrich E, Rose-John S, Gerhartz C, Mullberg J, Stoyan T, Yasukawa K, Heinrich PC, Graeve L . Identification of a region within the cytoplasmic domain of the interleukin-6 (IL-6) signal transducer gp130 important for ligand-induced endocytosis of the IL-6 receptor J Biol Chem 1994 269: 19014–19020

    CAS  PubMed  Google Scholar 

  19. Peters M, Muller AM, Rose-John S . Interleukin-6 and soluble interleukin-6 receptor: direct stimulation of gp130 and hematopoiesis Blood 1998 92: 3495–3504

    CAS  PubMed  Google Scholar 

  20. Puthier D, Derenne S, Barille S, Moreau P, Harousseau JL, Bataille R, Amiot M . Mcl-1 and Bcl-xL are co-regulated by IL-6 in human myeloma cells Br J Haematol 1999 107: 392–395

    Article  CAS  PubMed  Google Scholar 

  21. Schwarze MM, Hawley RG . Prevention of myeloma cell apoptosis by ectopic bcl-2 expression or interleukin 6-mediated up-regulation of bcl-xL Cancer Res 1995 55: 2262–226

    CAS  PubMed  Google Scholar 

  22. Nakajima K, Yamanaka Y, Nakae K, Kojima H, Ichiba M, Kiuchi N, Kitaoka T, Fukada T, Hibi M, Hirano T . A central role for Stat3 in IL-6-induced regulation of growth and differentiation in M1 leukemia cells EMBO J 1996 15: 3651–3658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Minami M, Inoue M, Wei S, Takeda K, Matsumoto M, Kishimoto T, Akira S . STAT3 activation is a critical step in gp130-mediated terminal differentiation and growth arrest of a myeloid cell line Proc Natl Acad Sci USA 1996 93: 3963–3966

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wen XY, Stewart AK, Sooknanan RR, Henderson G, Hawley TS, Reimold AM, Glimcher LH, Baumann H, Malek LT, Hawley RG . Identification of c-myc promoter-binding protein and X-box binding protein 1 as interleukin-6 target genes in human multiple myeloma cells Int J Oncol 1999 15: 173–178

    CAS  PubMed  Google Scholar 

  25. Vogel W, Ullrich A . Multiple in vivo phosphorylated tyrosine phosphatase SHP-2 engages binding to grb2 via tyrosine 584 Cell Growth Differ 1996 7: 1589–1597

    CAS  PubMed  Google Scholar 

  26. Feng G-S . Shp-2 tyrosine phosphatase: signaling one cell or many Exp Cell Res 1999 253: 47–54

    Article  CAS  PubMed  Google Scholar 

  27. Ohtani T, Ishihara K, Atsumi T, Nishida K, Kaneko Y, Miyata T, Itoh S, Narimatsu M, Maeda H, Fukada T, Itoh M, Okano H, Hibi M, Hirano T . Dissection of signaling cascades through gp130 in vivo: reciprocal roles for STAT3- and SHP2-mediated signals in immune response Immunity 2000 12: 95–105

    Article  CAS  PubMed  Google Scholar 

  28. Fukada T, Hibi M, Yamanaka Y, Takahashi-Tezuka M, Fujitani Y, Yamaguchi T, Nakajima K, Hirano T . Two signals are necessary for cell proliferation induced by a cytokine receptor gp130: involvement of STAT3 in anti-apoptosis Immunity 1996 5: 449–460

    Article  CAS  PubMed  Google Scholar 

  29. Fukada T, Ohtani T, Yoshida Y, Shirogane T, Nishida K, Nakajima K, Hibi M, Hirano T . STAT3 orchestrates contradictory signals in cytokine-induced G1 to S cell-cycle transition EMBO J 1998 17: 6670–6677

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Smithgall TE, Briggs SD, Schreiner S, Lerner EC, Cheng H, Wilson MB . Control of myeloid differentiation and survival by Stats Oncogene 2000 19: 2612–2618

    Article  CAS  PubMed  Google Scholar 

  31. Bonni A, Sun Y, Nadal-Vicens M, Bhatt A, Frank DA, Rozovsky I, Stahl N, Yancopoulos GD, Greenberg ME . Regulation of gliogenesis in the central nervous system by the JAK-STAT signaling pathway Science 1997 278: 477–483

    Article  CAS  PubMed  Google Scholar 

  32. Yanagisawa M, Nakashima K, Taga T . STAT3-mediated astrocyte differentiation from mouse fetal neuroepithelial cells by mouse oncostatin M Neurosci Lett 1999 269: 169–172

    Article  CAS  PubMed  Google Scholar 

  33. Urashima M, Teoh G, Chauhan D, Hoshi Y, Ogata A, Treon SP, Schlossman RL, Anderson KC . Interleukin-6 overcomes p21WAF1 upregulation and G1 growth arrest induced by dexamethasone and interferon-gamma in multiple myeloma cells Blood 1997 90: 279–289

    CAS  PubMed  Google Scholar 

  34. Morse L, Chen D, Franklin D, Xiong Y, Chen-Kiang S . Induction of cell cycle arrest and B cell terminal differentiation by CDK inhibitor p18(INK4c) and IL-6 Immunity 1997 6: 47–56

    Article  CAS  PubMed  Google Scholar 

  35. Stahl N, Farruggella TJ, Boulton TG, Zhong Z, Darnell JE Jr, Yancopoulos GD . Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors Science 1995 267: 1349–1353

    Article  CAS  PubMed  Google Scholar 

  36. Chauhan D, Pandey P, Hideshima T, Treon S, Raje N, Davies FE, Shima Y, Tai YT, Rosen S, Avraham S, Kharbanda S, Anderson KC . SHP2 mediates the protective effect of interleukin-6 against dexamethasone-induced apoptosis in multiple myeloma cells J Biol Chem 2000 275: 27845–27850

    CAS  PubMed  Google Scholar 

  37. Kovanen PE, Leonard WJ . Inhibitors keep cytokines in check Curr Biol 1999 9: R899–902

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by NIH grants CA21115 to the Eastern Cooperative Oncology Group and CA62242.

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Authors and Affiliations

  1. Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA

    W-C Cheung

  2. The Cancer Center, University of Minnesota, Minneapolis, MN, USA

    B Van Ness

  3. Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, MN, USA

    B Van Ness

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  1. W-C Cheung
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Cheung, WC., Van Ness, B. Distinct IL-6 signal transduction leads to growth arrest and death in B cells or growth promotion and cell survival in myeloma cells. Leukemia 16, 1182–1188 (2002). https://doi.org/10.1038/sj.leu.2402481

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