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Myeloma

Toll-like receptors mediate proliferation and survival of multiple myeloma cells

Leukemia volume 20, pages 1138–1144 (2006)Cite this article

Abstract

Multiple myeloma (MM) is an incurable B-cell malignancy characterized by accumulation of malignant plasma cells in bone marrow (BM) and recurrent or persistent infections. Toll-like receptors (TLRs) are essential in the host defense against infections and today 10 human TLRs (TLR1-TLR10) and one TLR-homolog (RP105) have been characterized. B cells express several TLRs (mainly TLR1, 6, 7, 9, 10 and RP105) and TLR-initiated responses in B cells include proliferation, anti-apoptosis effect and plasma cell (PC) differentiation. The present study was designed to analyze the role of TLRs in MM. We show that frequent expressions of TLRs were detected in cell lines from MM patients (minimum six TLRs in each). In comparison, only few TLRs (mainly TLR1 and or RP105) were found expressed in PCs from BM of healthy donors. In addition, TLR-specific ligands induce increased proliferation and survival of the MM cell lines, partially due to an autocrine interleukin-6 production. Importantly, we demonstrate that also PC from MM patients proliferates in response to TLR-specific ligands. In conclusion, TLR-ligands may contribute to increased growth and survival of MM cells in MM patients.

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References

  1. O'Connor BP, Gleeson MW, Noelle RJ, Erickson LD . The rise and fall of long-lived humoral immunity: terminal differentiation of plasma cells in health and disease. Immunol Rev 2003; 194: 61–76.

    Article  CAS  Google Scholar 

  2. Shapiro-Shelef M, Calame K . Plasma cell differentiation and multiple myeloma. Curr Opin Immunol 2004; 16: 226–234.

    Article  CAS  Google Scholar 

  3. Hideshima T, Richardson P, Anderson KC . Novel therapeutic approaches for multiple myeloma. Immunol Rev 2003; 194: 164–176.

    Article  CAS  Google Scholar 

  4. Seidl S, Kaufmann H, Drach J . New insights into the pathophysiology of multiple myeloma. Lancet Oncol 2003; 4: 557–564.

    Article  CAS  Google Scholar 

  5. Anderson KC, Shaughnessy Jr JD, Barlogie B, Harousseau JL, Roodman GD . Multiple myeloma. Hematology (Am Soc Hematol Educ Program) 2002, 214–240.

  6. Brenne AT, Baade RT, Waage A, Sundan A, Borset M, Hjorth-Hansen H . Interleukin-21 is a growth and survival factor for human myeloma cells. Blood 2002; 99: 3756–3762.

    Article  CAS  Google Scholar 

  7. Lauta VM . A review of the cytokine network in multiple myeloma: diagnostic, prognostic, and therapeutic implications. Cancer 2003; 97: 2440–2452.

    Article  CAS  Google Scholar 

  8. Jacobson DR, Zolla-Pazner S . Immunosuppression and infection in multiple myeloma. Semin Oncol 1986; 13: 282–290.

    CAS  PubMed  Google Scholar 

  9. Oken MM, Pomeroy C, Weisdorf D, Bennett JM . Prophylactic antibiotics for the prevention of early infection in multiple myeloma. Am J Med 1996; 100: 624–628.

    Article  CAS  Google Scholar 

  10. Akira S, Hemmi H . Recognition of pathogen-associated molecular patterns by TLR family. Immunol Lett 2003; 85: 85–95.

    Article  CAS  Google Scholar 

  11. Akira S . Mammalian Toll-like receptors. Curr Opin Immunol 2003; 15: 238.

    Article  CAS  Google Scholar 

  12. Bernasconi NL, Traggiai E, Lanzavecchia A . Maintenance of serological memory by polyclonal activation of human memory B cells. Science 2002; 298: 2199–2202.

    Article  CAS  Google Scholar 

  13. Bernasconi NL, Onai N, Lanzavecchia A . A role for Toll-like receptors in acquired immunity: upregulation of TLR9 by BCR triggering in naive B cells and constitutive expression in memory B cells. Blood 2003; 101: 4500–4504.

    Article  CAS  Google Scholar 

  14. Hornung V, Rothenfusser S, Britsch S, Krug A, Jahrsdorfer B, Giese T et al. Quantitative expression of Toll-like receptor 1-10 mRNA in cellular subsets of human peripheral blood mononuclear cells and sensitivity to CpG oligodeoxynucleotides. J Immunol 2002; 168: 4531–4537.

    Article  CAS  Google Scholar 

  15. Jung J, Yi AK, Zhang X, Choe J, Li L, Choi YS . Distinct response of human B cell subpopulations in recognition of an innate immune signal, CpG DNA. J Immunol 2002; 169: 2368–2373.

    Article  CAS  Google Scholar 

  16. Krieg AM . CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol 2002; 20: 709–760.

    Article  CAS  Google Scholar 

  17. Bourke E, Bosisio D, Golay J, Polentarutti N, Mantovani A . The Toll-like receptor repertoire of human B lymphocytes: inducible and selective expression of TLR9 and TLR10 in normal and transformed cells. Blood 2003; 102: 956–963.

    Article  Google Scholar 

  18. Bishop GA, Ramirez LM, Baccam M, Busch LK, Pederson LK, Tomai MA . The immune response modifier resiquimod mimics CD40-induced B cell activation. Cellular Immunol 2001; 208: 9–17.

    Article  CAS  Google Scholar 

  19. Jurk M, Heil F, Vollmer J, Schetter C, Krieg AM, Wagner H et al. Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat Immunol 2002; 3: 499.

    Article  CAS  Google Scholar 

  20. Peng SL . Signaling in B cells via Toll-like receptors. Curr Opin Immunol 2005; 17: 230–236.

    Article  CAS  Google Scholar 

  21. Borset M, Waage A, Brekke OL, Helseth E . TNF and IL-6 are potent growth factors for OH-2, a novel human myeloma cell line. Eur J Haematol 1994; 53: 31–37.

    Article  CAS  Google Scholar 

  22. Jarrossay D, Napolitani G, Colonna M, Sallusto F, Lanzavecchia A . Specialization and complementarity in microbial molecule recognition by human myeloid and plasmacytoid dendritic cells. Eur J Immunol 2001; 11: 3388–3393.

    Article  Google Scholar 

  23. Scheel B, Teufel R, Probst J, Carralot JP, Geginat J, Radsak M et al. Toll-like receptor-dependent activation of several human blood cell types by protamine-condensed mRNA. Eur J Immunol 2005; 35: 1557–1566.

    Article  CAS  Google Scholar 

  24. Rasmussen T, Theilgaard-Monch K, Hudlebusch HR, Lodahl M, Johnsen HE, Dahl IMS . Occurrence of dysregulated oncogenes in primary plasma cells representing consecutive stages of myeloma pathogenesis: indications for different disease entities. Br J Haematol 2003; 123: 253–262.

    Article  CAS  Google Scholar 

  25. Rasmussen T, Jensen L, Honore L, Andersen H, Johnsen HE . Circulating clonal cells in multiple myeloma do not express CD34 mRNA, as measured by single-cell and real-time RT-PCR assays. Br J Haematol 1999; 107: 818–824.

    Article  CAS  Google Scholar 

  26. Durie BG, Salmon SE . A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer 1975; 36: 842–854.

    Article  CAS  Google Scholar 

  27. Greipp PR, San MJ, Durie BG, Crowley JJ, Barlogie B, Blade J et al. International staging system for multiple myeloma. J Clin Oncol 2005; 23: 3412–3420.

    Article  Google Scholar 

  28. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA . Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature 2001; 413: 732–738.

    Article  CAS  Google Scholar 

  29. Hirschfeld M, Ma Y, Weis JH, Vogel SN, Weis JJ . Cutting edge: repurification of lipopolysaccharide eliminates signaling through both human and murine Toll-like receptor 2. J Immunol 2000; 165: 618–622.

    Article  CAS  Google Scholar 

  30. Hayashi F, Smith KD, Ozinsky A, Hawn TR, Yi EC, Goodlett DR et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature 2001; 410: 1099–1103.

    Article  CAS  Google Scholar 

  31. Mita Y, Dobashi K, Endou K, Kawata T, Shimizu Y, Nakazawa T et al. Toll-like receptor 4 surface expression on human monocytes and B cells is modulated by IL-2 and IL-4. Immunol Lett 2002; 81: 71–75.

    Article  CAS  Google Scholar 

  32. Zarember KA, Godowski PJ . Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J Immunol 2002; 168: 554–561.

    Article  CAS  Google Scholar 

  33. Chen W, Wang J, An H, Zhou J, Zhang L, Cao X . Heat shock up-regulates TLR9 expression in human B cells through activation of ERK and NF-kappaB signal pathways. Immunol Lett 2005; 98: 153–159.

    Article  CAS  Google Scholar 

  34. Gado K, Domjan C, Hegyesi H, Falus A . Role of interleukin-6 in the pathogenesis of multiple myeloma. Cell Biol Int 2000; 24: 195–209.

    Article  CAS  Google Scholar 

  35. Borset M, Helseth E, Naume B, Waage A . Lack of IL-1 secretion from human myeloma cells highly purified by immunomagnetic separation. Br J Haematol 1993; 85: 446–451.

    Article  CAS  Google Scholar 

  36. Wagner M, Poeck H, Jahrsdoerfer B, Rothenfusser S, Prell D, Bohle B et al. IL-12p70-dependent Th1 induction by human B cells requires combined activation with CD40L and CpG DNA. J Immunol 2004; 172: 954–963.

    Article  CAS  Google Scholar 

  37. Divanovic S, Trompette A, Atabani SF, Madan R, Golenbock DT, Visintin A et al. Negative regulation of Toll-like receptor 4 signaling by the Toll-like receptor homolog RP105. Nat Immunol 2005; 6: 571–578.

    Article  CAS  Google Scholar 

  38. Ogata H, Su I, Miyake K, Nagai Y, Akashi S, Mecklenbrauker I et al. The Toll-like receptor protein RP105 regulates lipopolysaccharide signaling in B cells. J Exp Med 2000; 192: 23–29.

    Article  CAS  Google Scholar 

  39. Jahrsdorfer B, Muhlenhoff L, Blackwell SE, Wagner M, Poeck H, Hartmann E et al. B-cell lymphomas differ in their responsiveness to CpG oligodeoxynucleotides. Clin Cancer Res 2005; 11: 1490–1499.

    Article  CAS  Google Scholar 

  40. Jahrsdorfer B, Wooldridge JE, Blackwell SE, Taylor CM, Griffith TS, Link BK et al. Immunostimulatory oligodeoxynucleotides induce apoptosis of B cell chronic lymphocytic leukemia cells. J Leukoc Biol 2005; 77: 378–387.

    Article  Google Scholar 

  41. Zhong S, Yeo W, Tang M, Liu CL, Lin XR, Ho WM et al. Frequent detection of the replicative form of TT virus DNA in peripheral blood mononuclear cells and bone marrow cells in cancer patients. J Med Virol 2002; 66: 428–434.

    Article  CAS  Google Scholar 

  42. Beg AA . Endogenous ligands of Toll-like receptors: implications for regulating inflammatory and immune responses. Trends Immunol 2002; 23: 509–512.

    Article  CAS  Google Scholar 

  43. Kariko K, Ni HP, Capodici J, Lamphier M, Weissman D . mRNA is an endogenous ligand for Toll-like receptor 3. J Biol Chem 2004; 279: 12542–12550.

    Article  CAS  Google Scholar 

  44. Tsan MF, Gao B . Endogenous ligands of Toll-like receptors. J Leukoc Biol 2004; 76: 514–519.

    Article  CAS  Google Scholar 

  45. Rifkin IR, Leadbetter EA, Busconi L, Viglianti G, Marshak-Rothstein A . Toll-like receptors, endogenous ligands, and systemic autoimmune disease. Immunol Rev 2005; 204: 27–42.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Marianne Lodahl at Herlev Hospital, University of Copenhagen, Denmark for technical assistance and Dr med. Anders Waage at St Olavs Hospital, Trondheim University Hospital, Norway for providing some of the patient material. This work was supported by grants from the Central Norway Regional Health Authority, Norwegian University of Science and Technology, the Norwegian Cancer Society and the Norwegian Research Council.

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Authors and Affiliations

  1. Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway

    J Bohnhorst, S H Moen, M Fløttum, M Børset, T Espevik & A Sundan

  2. Department of Hematology L54P4, Herlev Hospital, University of Copenhagen, Herlev, Denmark

    T Rasmussen & L Knudsen

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  1. J Bohnhorst
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Correspondence to J Bohnhorst.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Bohnhorst, J., Rasmussen, T., Moen, S. et al. Toll-like receptors mediate proliferation and survival of multiple myeloma cells. Leukemia 20, 1138–1144 (2006). https://doi.org/10.1038/sj.leu.2404225

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