Skip to main content
Log in

Interleukin-6 production in B-cell neoplasias and Castleman's disease: Evidence for an additional paracrine loop

  • Original Article
  • Published:
Annals of Hematology Aims and scope Submit manuscript

Summary

Functioning as a B-cell growth and differentiation factor, interleukin-6 (IL-6) may play an important role in the pathophysiology of B-cell tumors. The capacity for IL-6 secretion was evaluated in 58 patients with various B-cell leukemias/lymphomas and in four patients with Castleman's disease (CMD). Cell populations from various sites including peripheral blood, bone marrow, lymph nodes, and osteolytic bone lesions were cultured and tested for spontaneous or IL-1Β/ TNFα-induced IL-6 production in a sensitive bioassay. No significant IL-6 levels were released by the tumor cells in any of the B-cell leukemias or lymphomas tested, including hairy cell leukemia (HCL) and B-cell chronic lymphocytic leukemia (B-CLL). In contrast, purified malignant plasma cells were found to secrete IL-6, strengthening the idea that an autocrine pathway for growth regulation in multiple myeloma (MM) exists. For the first time, in several patients with CMD, peripheral blood cells were shown to produce extremely high levels of IL-6, the pathogenetic significance of which remains to be elucidated. However, similar observations were very occasionally made in MM patients. Therapy with corticosteroids strongly inhibited this IL-6 production. These data provide evidence for autocrine and possibly an additional paracrine regulatory loop in plasma cell neoplasias and CMD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Aarden LA, De Groot ER, Schaap OL, Lansdorp PM (1987) Production of hybridoma growth factor by human monocytes. Eur J Immunol 17:1411–1416

    Google Scholar 

  2. Aguilar-Santelises M, Magnusson R, Svenson SB, Loftenius A, Andersson B, Mellstedt H, Jondal M (1991) Expression of interleukin-1α, interleukin-1Β and interleukin-6 in chronic B lymphocytic leukaemia (B-CLL) cells from patients at different stages of disease progression. Clin Exp Immunol 84:422–428

    Google Scholar 

  3. Asano S, Okano A, Ozawa K, Nakahata T, Ishibashi T, Koike K, Kimura H, Tanioka Y, Shibuya A, Hirano T, Kishimoto T, Takaku F, Akiyama Y (1990) In vivo effects of recombinant human interleukin-6 in primates: stimulated production of platelets. Blood 75:1602–1605

    Google Scholar 

  4. Bauer J, Ganter U, Geiger T, Jacobshagen U, Hirano T, Matsuda T, Kishimoto T, Andus T, Acs G, Gerok W, Ciliberto G (1988) Regulation of interleukin-6 expression in cultured human blood monocytes and monocyte-derived macrophages. Blood 72:1134–1140

    Google Scholar 

  5. Beck JT, Hsu S-M, Wijdenes J, Bataille R, Klein B, Vesole D, Hayden K, Jagannath S, Barlogie B (1994) Brief report: alleviation of systemic manifestations of Castleman's disease by monoclonal anti-interleukin-6 antibody. N Engl J Med 330:602–605

    Google Scholar 

  6. Biondi A, Rossi V, Bassan R, Barbui T, Bettoni S, Sironi M, Mantovani A, Rambaldi A (1989) Constitutive expression of the interleukin-6 gene in chronic lymphocytic leukemia. Blood 73:1279–1284

    Google Scholar 

  7. Brandt SJ, Bodine DM, Dunbar CE, Nienhuis AW (1990) Dysregulated interleukin-6 expression produces a syndrome resembling Castleman's disease in mice. J Clin Invest 86:592–599

    Google Scholar 

  8. Caligaris-Cappio F, Bergui L, Gregoretti MG, Gaidano G, Gaboli M, Schena M, Zallone AZ, Machisio PC (1991) Role of bone marrow stromal cells in the growth of human multiple myeloma. Blood 77:2688–2693

    Google Scholar 

  9. Carter A, Merchav S, Silvian-Draxler I, Tatarsky I (1990) The role of interleukin-1 and tumour necrosis factor-α in human multiple myeloma. Br J Haematol 74:424–431

    Google Scholar 

  10. Durie BGM, Salmon SE (1975) A clinical staging system for multiple myeloma. Correlations of measured myeloma cell mass with presenting clinical features, response to treatment and survival. Cancer 36:842–854

    Google Scholar 

  11. Freeman GJ, Freedman AS, Rabinowe SN, Segil JM, Horowitz J, Rosen K, Whitman JF, Nadler LM (1989) Interleukin-6 gene expression in normal and neoplastic B cells. J Clin Invest 83:1512–1518

    Google Scholar 

  12. Gramatzki M, Burger R, Kraus J, Lauer U, Rohwer P, Eger G, Kalden JR, Henschke F (1991) Monoclonal antibodies EBU-141 (CDw75) and EBU-65 allow reliable distinction between mature and pre-B-cell tumors in suspension and on tissue sections. Ann Hematol 63:20–26

    Google Scholar 

  13. Hata H, Xiao H, Petrucci MT, Woodliff J, Chang R, Epstein J (1993) Interleukin-6 gene expression in multiple myeloma: a characteristic of immature tumor cells. Blood 81:3357–3364

    Google Scholar 

  14. Helfgott DC, May LT, Sthoeger Z, Tamm I, Sehgal PB (1987) Bacterial lipopolysaccharide (endotoxin) enhances expression and secretion ofΒ 2 interferon by human fibroblasts. J Exp Med 166:1300–1309

    Google Scholar 

  15. Heslop HE, Bianchi ACM, Cordingley FT, Turner M, De Mel WCP, Hoffbrand AV, Brenner MK (1990) Effects of interferonα on autocrine growth factor loops in B lymphoproliferative disorders. J Exp Med 172:1729–1734

    Google Scholar 

  16. Hirano T, Akira S, Taga T, Kishimoto T (1990) Biological and clinical aspects of interleukin 6. Immunol Today 11:443–449

    Google Scholar 

  17. Ishikawa H, Tanaka H, Iwato K, Tanabe O, Asaoku H, Nobuyoshi M, Yamamoto I, Kawano M, Kuramoto A (1990) Effect of glucocorticoids on the biologic activities of myeloma cells: inhibition of interleukin-1Β osteoclast activating factor-induced bone resorption. Blood 75:715–720

    Google Scholar 

  18. Kawano M, Hirano T, Matsuda T, Taga T, Horii Y, Iwato K, Asaoku H, Tang B, Tanabe O, Tanaka H, Kuramoto A, Kishimoto T (1988) Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature 332:83–85

    Google Scholar 

  19. Kawano M, Tanaka H, Ishikawa H, Nobuyoshi M, Iwato K, Asaoku H, Tanabe O, Kuramoto A (1989) Interleukin-1 accelerates autocrine growth of myeloma cells through interleukin-6 in human myeloma. Blood 73:2145–2148

    Google Scholar 

  20. Kawano M, Yamamoto I, Iwato K, Tanaka H, Asaoku H, Tanabe O, Ishikawa H, Nobuyoshi M, Ohmoto Y, Hirai Y, Kuramoto A (1989) Interleukin-1 beta rather than lymphotoxin as the major bone resorbing activity in human multiple myeloma. Blood 73:1646–1649

    Google Scholar 

  21. Kishimoto T (1989) The biology of interleukin-6. Blood 74:1–10

    Google Scholar 

  22. Klein B, Wijdenes J, Zhang X-G, Jourdan M, Boiron J-M, Brochier J, Liautard J, Merlin M, Clement C, Morel-Fournier B, Lu Z-Y, Mannoni P, Sany J, Bataille R (1991) Murine anti-interleukin-6 monoclonal antibody therapy for a patient with plasma cell leukemia. Blood 78:1198–1204

    Google Scholar 

  23. Klein B, Zhang X-G, Jourdan M, Content J, Houssiau F, Aarden L, Piechaczyk M, Bataille R (1989) Paracrine rather than autocrine regulation of myeloma-cell growth and differentiation by interleukin-6. Blood 73:517–526

    Google Scholar 

  24. Lahat N, Aghai E, Maroun B, Kinarty A, Quitt M, Froom P (1991) Increased spontaneous secretion of IL-6 from B cells of patients with B chronic lymphatic leukaemia (B-CLL) and autoimmunity. Clin Exp Immunol 85:302–306

    Google Scholar 

  25. Lang RA, Burgess W (1990) Autocrine growth factors and tumourigenic transformation. Immunol Today 11:244–249

    Google Scholar 

  26. Leger-Ravet MB, Peuchmaur M, Devergne O, Audouin J, Raphael M, Van Damme J, Galanaud P, Diebold J, Emilie D (1991) Interleukin-6 gene expression in Castleman's disease. Blood 78:2923–2930

    Google Scholar 

  27. Sporn MB, Roberts AB (1985) Autocrine growth factors and cancer. Nature 313:745–747

    Google Scholar 

  28. Stansfeld AG, Diebold J, Noel H, Kapanci Y, Rilke F, Kelenyi G, Sundstrom C, Lennert K, van Unnik JAM, Mioduszewska O, Wright DH (1988) Updated Kiel classification for lymphomas. Lancet 1:292–293

    Google Scholar 

  29. Suematsu S, Matsuda T, Aozasa K, Akira S, Nakano N, Ohno S, Miyazaki J, Yamamura K, Hirano T, Kishimoto T (1989) IgG1 plasmacytosis in interleukin-6 transgenic mice. Proc Natl Acad Sci USA 86:7547–7551

    Google Scholar 

  30. Tobler A, Meier R, Scitz M, Dewald B, Baggiolini M, Fey MF (1992) Glucocorticoids downregulate gene expression of GMCSF, NAP-1/IL-8, and IL-6, but not of M-CSF in human fibroblasts. Blood 79:45–51

    Google Scholar 

  31. Van Damme J, Opdenakker G, Simpson RJ, Rubira MR, Cayphas S, Vink A, Billiau A, Van Snick J (1987) Identification of the human 26-kD protein, interferonΒ 2 (IFN-Β 2), as a B cell hybridoma/plasmacytoma growth factor induced by interleukin 1 and tumor necrosis factor. J Exp Med 165:914–919

    Google Scholar 

  32. Van Snick J, Vink A, Cayphas S, Uyttenhove C (1987) Interleukin-HP1, a T-cell-derived hybridoma growth factor that supports the in vitro growth of murine plasmacytomas. J Exp Med 165:641–649

    Google Scholar 

  33. Vink A, Coulie P, Warnier G, Renauld JC, Stevens M, Donckers D, Van Snick J (1990) Mouse plasmacytoma growth in vivo: enhancement by interleukin 6 (IL-6) and inhibition by antibodies directed against IL-6 or its receptor. J Exp Med 172:997–1000

    Google Scholar 

  34. Weber J, Yang JC, Topalian SL, Parkinson DR, Schwartzentruber DS, Ettinghausen SE, Gunn H, Mixon A, Kim H, Cole D, Levin R, Rosenberg SA (1993) Phase-I trial of subcutaneous interleukin-6 in patients with advanced malignancies. J Clin Oncol 11:499–506

    Google Scholar 

  35. Wendler J, Burger R, Stö\ H, Becker W, Feller AC, Kalden JR, Gramatzki M (1991) B-cell angiotropic lymphoma with bone involvement and paracrine IL-6 production. Onkologie 15 [Suppl 2]:172

    Google Scholar 

  36. Yabuhara A, Komiyama A (1990) Castleman's disease and interleukin 6. Leukemia Lymphoma 2:369–380

    Google Scholar 

  37. Yoshizaki K, Matsuda T, Nishimoto N, Kuritani T, Taeho L, Aozasa K, Nakahate T, Kawai H, Tagoh H, Komori T, Kishimoto S, Hirano T, Kishimoto A (1989) Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman's disease. Blood 74:1360–1367

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Burger, R., Wendler, J., Antoni, K. et al. Interleukin-6 production in B-cell neoplasias and Castleman's disease: Evidence for an additional paracrine loop. Ann Hematol 69, 25–31 (1994). https://doi.org/10.1007/BF01757344

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF01757344

Key words

Navigation