Skip to main content
SpringerLink
Log in

Interleukin-6: biologic properties and role in lymphoproliferative disorders

  • Chapter
Molecular Genetics and Therapy of Leukemia

Part of the book series: Cancer Treatment and Research ((CTAR,volume 84))

Abstract

Interleukin-6 (IL-6) is a cytokine that exemplifies the multifunctional nature common to all interleukins [1]. Due to its broad range of actions in many systems, IL-6 has been and remains the focus of intense investigation in a number of diverse research fields. Indeed, prior to its complete characterization, the molecule was variously referred to as interferon (IFN) — β2 [2], B-cell stimulatory factor 2 [3], human hybridomaplasmacytoma growth factor [4], or hepatocyte-stimulatory factor [5]. Although such functional designations clearly and succintly conveyed a single specific action and were historically very useful, they initially led to some confusion among researchers, and it was not until the determination of the amino-acid sequence of each of these ‘factors’ that their common identity was recognized and the uniform use of the designation IL-6 was adopted (reviewed in [6]). With the more rapid cloning and production of recombinant molecules, such confusion with terminology rarely exists with cytokines and growth factors discovered in more recent years.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 259.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 329.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 329.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Paul WE, Kishimoto T, Melchers F, Metcalf D, Mosmann T, Oppenheim J, Ruddle N, Van Snick J (1992). Nomeclature for secreted regulatory proteins of the immune system (interleukins). Clin Exp Immunol 88:367.

    Article  PubMed  CAS  Google Scholar 

  2. Weissenbach J, Chernajovsky Y, Zeevi M, Shulman L, Sorecq H, Nir U, Wallach D, Perricaudet M, Tiollais P, Revel M (1980). Two interferon mRNAs in human fibroblasts: in vitro translation and Escherichia coli cloning studies. Proc Natl Acad Sci USA 77:7152–7156.

    Article  PubMed  CAS  Google Scholar 

  3. Hirano T, Yasukawa K, Harada H, Taga T, Watanabe Y, Matsuda T, Kashiwamura S-I, Nakajima K, Koyama K, Iwamatsu A, Tsunasawa S, Sakiyama F, Matsui H, Takahara Y, Taniguchi T, Kishimoto T (1986). Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature 324:73–76.

    Article  PubMed  CAS  Google Scholar 

  4. Van Damme J, Cayphas S, Opdenakker G, Billiau A, Van Snick J (1987). Interleukin-1 and poly(rl).poly(rC) induce production of a hybridoma growth factor by human fibroblasts. Eur J Immunol 17:1–7.

    Article  PubMed  Google Scholar 

  5. Gauldie J, Richards C, Harnish D, Landsdorp P, Baumann H (1987). Interferon-β 2/BSF-2 shares identity with monocyte-derived hepatocyte stimulatory factor (HSF) and regulates the major acute phase protein response in liver cells. Proc Natl Acad Sci USA 84:9035–9039.

    Article  Google Scholar 

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

    Article  PubMed  Google Scholar 

  7. Klein B, Zhang X-G, Jourdan M, Boiron J-M, Portier M, Lu Z-Y, Wijdenes J, Brochier J, Bataille R (1990). Interleukin-6 is the central tumor growth factor in vitro and in vivo in multiple myeloma. Eur Cytokine Network 1:193–201.

    CAS  Google Scholar 

  8. Hirano T (1991). Interleukin 6 (IL-6) and its receptor: their role in plasma cell neoplasias. Int J Cell Cloning 9:166–184.

    Article  PubMed  CAS  Google Scholar 

  9. Kawano M, Tanabe O (1993). Involvement of IL-6 in development of myeloma. Gann Mono Cancer Res 40:23–34.

    CAS  Google Scholar 

  10. Klein B (1995). Cytokine, cytokine receptors, transduction signals, and oncogenes in human multiple myeloma. Semin Hematol 32:4–19.

    PubMed  CAS  Google Scholar 

  11. Muraguchi A, Hirano T, Tang B, Matsuda T, Horri Y, Nakajima K, Kishimoto T (1988). The essential role of B cell stimulatory factor 2 (BSF-2/IL-6) for the terminal differentiation of B cells. J Exp Med 167:332–344.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  13. Takatsuki F, Okano A, Suzuki C, Chieda R, Takahara Y, Hirano T, Kishimoto T, Hamuro J, Akiyama Y (1988). Human recombinant interleukin 6/B cell stimulatory factor 2 (IL-6/BSF-2) augments murine antigen-specific antibody responses in vitro and in vivo. J Immunol 141:3072–3077.

    PubMed  CAS  Google Scholar 

  14. Kopf M, Baumann H, Freer G, Freudenberg M, Lamers M, Kishimoto T, Zinkernagel R, Bluethmann H, Köhler G (1994). Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature 368:339–342.

    Article  PubMed  CAS  Google Scholar 

  15. Ramsay AJ, Husband AJ, Ramshaw IA, Bao S, Matthaei KI, Koehler G, Kopf M (1994). The role of interleukin-6 in mucosal IgA antibody responses in vivo. Science 264:561–563.

    Article  PubMed  CAS  Google Scholar 

  16. Wognum AW, van Gils FCJM, Wagemaker G (1993). Flow cytometric detection of receptors for interleukin-6 on bone marrow and peripheral blood cells of humans and rhesus monkeys. Blood 81:2036–2043.

    PubMed  CAS  Google Scholar 

  17. McKinstry W, Metcalf D, Li C-L (1994). Distribution of IL-6 receptors on murine hemopoietic and lymphoid cells and the anomalous action of IL-6 in stimulating granulocytic proliferation. Leukemia 8:1726–1733.

    PubMed  CAS  Google Scholar 

  18. Xia X, Lee H-K, Clark SC, Choi YS (1989). Recombinant interleukin (IL) 2-induced human B cell differentiation is mediated by autocrine IL 6. Eur J Immunol 19:2275–2281.

    Article  PubMed  CAS  Google Scholar 

  19. 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.

    Article  PubMed  CAS  Google Scholar 

  20. Takai Y, Wong GG, Clark SC, Burakoff SJ, Herrmann SH (1988). B cell stimulatory factor-2 is involved in the differentiation of cytotoxic T lymphocytes. J Immunol 140:508–512.

    PubMed  CAS  Google Scholar 

  21. Garman RD, Jacobs KA, Clark SC, Raulet DH (1987). B-cell stimulatory factor 2 (β2 interferon) functions as a second signal for interleukin 2 production by mature murine T cells. Proc Natl Acad Sci USA 84:7629–7633.

    Article  PubMed  CAS  Google Scholar 

  22. Ikebuchi K, Wong GG, Clark SC, Ihle JN, Hirai Y, Ogawa M (1987). Interleukin-6 enhancement of interleukin-3-dependent proliferation of multipotential hemopoietic progenitors. Proc Natl Acad Sci USA 84:9035–9039.

    Article  PubMed  CAS  Google Scholar 

  23. Koike K, Nakahata T, Takagi M, Kobayashi T, Ishiguro A, Tsuji K, Naganuma K, Okano A, Akiyama Y, Akabane T (1988). Synergism of BSF-2/interleukin-6 and interleukin 3 on development of multipotential hemopoietic progenitors in serum-free culture. J Exp Med 168:879–890.

    Article  PubMed  CAS  Google Scholar 

  24. Leary AG, Ikebuchi K, Hirai Y, Wong GG, Yang Y-C, Clark SC, Ogawa M (1988). Synergism between interleukin-6 and interleukin-3 in supporting proliferation of human hematopoietic stem cells: comparison with interleukin-1. Blood 71:1759–1763.

    PubMed  CAS  Google Scholar 

  25. Hoang T, Haman A, Goncalves O, Wong GG, Clark SC (1988). Interleukin-6 enhances growth factor-dependent proliferation of the blast cells of acute myeloblastic leukemia. Blood 72:823–826.

    PubMed  CAS  Google Scholar 

  26. Caraciolo D, Clark SC, Rovera G (1989). Human interleukin-6 supports granulocytic differentiation of hematopoietic progenitor cells and acts synergistically with GM-CSF. Blood 73:666–670.

    Google Scholar 

  27. Bot FJ, van Eijk L, Broeders L, Aarden LA, Löwenberg B (1989). Interleukin-6 synergizes with M-CSF in the formation of macrophage colonies from purified human marrow progenitor cells. Blood 73:435–437.

    PubMed  CAS  Google Scholar 

  28. Haylock DN, To LB, Dowse TL, Makino S, Juttner CA, Simmons PJ (1993). Ex vivo expansion and maturation of peripheral blood stem and progenitor cells for transplantation. Blood 82 (Suppl l):483a (Abstr. 1916).

    Google Scholar 

  29. Gordon MS, Hoffman R (1992). Growth factors affecting human thrombocytopoiesis: potential agents for the treatment of thrombocytopenia. Blood 80:302–307.

    PubMed  CAS  Google Scholar 

  30. Debili N, Massé J-M, Katz A, Guichard J, Breton-Gorius J, Vainchenker W (1993). Effects of recombinant hematopoietic growth factors interleukin-3, interleukin-6, stem cell factor, and leukemia inhibitory factor on the megakaryocytic differentiation of CD34+ cells. Blood 82:84–95.

    PubMed  CAS  Google Scholar 

  31. Lok S, Foster DC (1994). The structure, biology and potential therapeutic applications of recombinant thrombopoietin. Stem Cells 12:586–598.

    Article  PubMed  CAS  Google Scholar 

  32. Black K, Garrett IR, Mundy GR (1991). Chinese hamster ovarian cells transfected with the murine interleukin-6 gene cause hypercalcemia as well as cachexia, leukocytosis and thrombocytosis in tumor-bearing nude mice. Endocrinology 128:2657–2659.

    Article  PubMed  CAS  Google Scholar 

  33. Hawley RG, Fong AZC, Burns BF, Hawley TS (1992). Transplantable myeloproliferative disease induced in mice by an interleukin 6 retrovirus. J Exp Med 176:1149–1163.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  35. Weber J, Yang JC, Topalian SL, Parkinson DR, Schwartentruber DS, Ettinghausen SE, Gunn H, Mixon A, Kin 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.

    PubMed  CAS  Google Scholar 

  36. Weber J, Gunn H, Yang J, Parkinson D, Topalian S, Schwartzentruber D, Ettinghausen S, Levitt D, Rosenberg SA (1994). A phase I trial of intravenous interleukin-6 in patients with advanced cancer. J Immunother 15:292–302.

    Article  CAS  Google Scholar 

  37. van Gameran MM, Willemse PHB, Mulder NH, Limburg PC, Groen HJM, Vellenga E, de Vries EGE (1994). Effects of recombinant human interleukin-6 in cancer patients: A phase I-II study. Blood 84:1434–1441.

    Google Scholar 

  38. Atkins MB, Kappler K, Mier JW, Isaacs RE, Berkman EM (1994). Interleukin-6 associated anemia: determination of the underlying mechanism. Proc Am Soc Clin Oncol 13:295 (Abstr. 958).

    Google Scholar 

  39. Emilie D, Wijdenes J, Gisselbrecht C, Jarrousse B, Billaud E, Blay J-Y, Gabarre J, Gaillard J-P, Brochier J, Raphael M, Boue F, Galanaud P (1994). Administration of an anti-interleukin-6 monoclonal antibody to patients with acquired immunodeficiency syndrome and lymphoma: effect on lymphoma growth and on B clinical symptoms. Blood 84:2472–2479.

    PubMed  CAS  Google Scholar 

  40. 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.

    PubMed  CAS  Google Scholar 

  41. Audus T, Geiger T, Hirano T (1988). Action of recombinant human interleukin 6, interleukin 1, and tumor necrosis factor on the mRNA induction of acute-phase proteins. Eur J Immunol 18:739–746.

    Article  Google Scholar 

  42. Morrone G, Ciliberto G, Oliviero S, Arcone R, Dente L, Content J, Cortese R (1988). Recombinant interleukin 6 regulates the transcriptional activation of a set of human acute phase genes. J Biol Chem 263:12554–12558.

    PubMed  CAS  Google Scholar 

  43. Heinrich PC, Castell JV, Andus T (1990). Interleukin-6 and the acute phase response. Biochem J 265:621–636.

    PubMed  CAS  Google Scholar 

  44. Oldenburg HSA, Rogy MA, Lazarus DD, Van Zee KJ, Keeler BP, Chizzonite RA, Lowry SF, Moldawer LL (1993). Cachexia and the acute-phase protein response in inflammation are regulated by interleukin-6. Eur J Immunol 23:1889–1894.

    Article  PubMed  CAS  Google Scholar 

  45. Kobune M, Kohgo Y, Kato J, Miyazaki E, Nitsu Y (1994). Interleukin-6 enhances hepatic transferrin uptake and ferritin expression in rats. Hepatology 19:1468–1475.

    Article  PubMed  CAS  Google Scholar 

  46. Fattori E, Cappelletti M, Costa P, Sellitto C, Cantoni L, Carelli M, Faggioni R, Fantuzzi G, Ghezzi P, Poli V (1994). Defective inflammatory response in interleukin-6 deficient mice. J Exp Med 180:1243–1250.

    Article  PubMed  CAS  Google Scholar 

  47. Helle M, Brakenhoff JPJ, De Groot ER, Aarden LA (1988). Interleukin 6 is involved in interleukin 1-induced activities. Eur J Immunol 18:957–959.

    Article  PubMed  CAS  Google Scholar 

  48. Engel A, Kern WV, Mürdter G, Kern P (1994). Kinetics and correlation with body temperature of circulating interleukin-6, interleukin-8, tumor necrosis factor alpha and interleukin-1 beta in patients with fever and neutropenia. Infection 22:160–164.

    Article  PubMed  CAS  Google Scholar 

  49. Tanaka M, Miyazaki H, Takeda Y, Takeo S (1993). Detection of serum cytokine levels in experimental cancer cachexia of colon 26 adenocarcinoma-bearing mice. Cancer Lett 72:65–70.

    Article  PubMed  CAS  Google Scholar 

  50. Strassman G, Fong M, Kenney JS, Jacob CO (1992). Evidence for the involvement of interleukin 6 in experimental cancer cachexia. J Clin Invest 89:1681–1684.

    Article  Google Scholar 

  51. 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.

    Article  PubMed  CAS  Google Scholar 

  52. Goodman MN (1994). Interleukin-6 induces skeletal muscle protein breakdown in rats. Proc Soc Exp Biol Med 205:182–185.

    PubMed  CAS  Google Scholar 

  53. Löwik CWGM (1992). Differentiation inducing factors: leukemia inhibitory factor and interleukin-6. In Gowen M (ed), Cytokines and Bone Metabolism. CRC Press: Boca Raton, FL, pp. 299–324.

    Google Scholar 

  54. Jilka RL, Hangoc G, Girasole G, Paseri G, Williams DC, Abrams JS, Boyce B, Broxmeyer H, Manolagas SC (1992). Increased osteoclast development after estrogen loss: mediation by interleukin-6. Science 257:88–91.

    Article  PubMed  CAS  Google Scholar 

  55. Manolagas SC, Jilka RL (1995). Bone marrow, cytokines, and bone remodelling: emerging insights into the pathophysiology of osteoporosis. N Engl J Med 332:305–311.

    Article  PubMed  CAS  Google Scholar 

  56. Yoneda T, Nakai M, Moriyama K, Scott L, Ida N, Kunitomo T, Mundy G (1993). Neutralizing antibodies to human interleukin 6 reverse hypercalcemia associated with a human squamous carcinoma. Cancer Res 53:737–740.

    PubMed  CAS  Google Scholar 

  57. Reddy SV, Takahashi S, Dallas M, Williams RE, Neckers L, Roodman GD (1994). Interleukin-6 antisense deoxyoligonucleotides inhibit bone resorption by giant cells from human giant cell tumors of bone. J Bone Min Res 9:753–757.

    Article  CAS  Google Scholar 

  58. Rosol TJ, Capen CC (1992). Mechanisms of cancer-induced hypercalcemia. Lab Invest 67:680–702.

    PubMed  CAS  Google Scholar 

  59. Seymour JF, Gagel RF (1993). Calcitriol: the major humoral mediator of hypercalcemia in Hodgkin’s disease and non-Hodgkin’s lymphomas. Blood 82:1383–1394.

    PubMed  CAS  Google Scholar 

  60. Jones TH (1994). Interleukin-6: an endocrine cytokine. Clin Endocrinol 40:703–713.

    Article  CAS  Google Scholar 

  61. Navarra P, Tsagarakis S, Faria MS, Rees LH, Besser GM, Grossman AB (1991). Interleukin-1 and interleukin-6 stimulate the release of corticotropin-releasing hormone-41 from rat hypothalamus in vitro via an ecosanoid cyclooxygenase pathway. Endocrinology 128:34–44.

    Article  Google Scholar 

  62. Spangelo BL, Judd AM, Isakson PC, MacLeod RM (1991). Interleukin-6 stimulates anterior pituitary hormone release in vitro. Endocrinology 125:575–577.

    Article  Google Scholar 

  63. Salas MA, Evans SW, Levell MJ, Whicher JT (1990). Interleukin-6 and ACTH act synergis-tically to stimulate the release of corticosterone from adrenal gland cells. Clin Exp Immunol 79:470–473.

    Article  PubMed  CAS  Google Scholar 

  64. Syners L, Fontaine V, Content J (1989). Modulation of interleukin-6 receptors in human cells. Ann N Y Acad Sci 557:388–395.

    Article  Google Scholar 

  65. Marinkovic S, Jahreis GP, Wong GG, Baumann H (1989). IL-6 modulates the synthesis of a specific set of acute phase plasma proteins in vivo. J Immunol 142:808–812.

    PubMed  CAS  Google Scholar 

  66. Kunicka JE, Talle MA, Denhardt GH, Brown M, Prince LA, Goldstein G (1993). Immunosuppression by glucocorticoids: inhibition of production of multiple lymphokines by an in vivo administration of dexamethasone. Cell Immunol 149:39–49.

    Article  PubMed  CAS  Google Scholar 

  67. Olencki T, Budd GT, Murthy S, Finke J, Herzog P, McLain D, Tubbs R, Tuaason L, Edinger M, Levitt D, Bukowski RM (1993). Phase 1A/1B trial of rhIL-6 in patients with refractory malignancies: an immunomodulatory cytokine. J Immunother 14:362 (abstract).

    Article  Google Scholar 

  68. Tanabe O, Akira S, Kamiya T, Wong GG, Hirano T, Kishimoto T (1988). Genomic structure of the murine IL-6 gene: high degree conservation of potential regulatory sequences between mouse and human. J Immunol 141:3875–3881.

    PubMed  CAS  Google Scholar 

  69. Brakenhoff JPJ, Hart M, Aarden LA (1989). Analysis of human IL-6 mutants expressed in Escherichia coli — biologic activities are not affected by deletion of amino acids 1–28. J Immunol 143:1115–1122.

    Google Scholar 

  70. Bazan JF (1990). Haemopoietic receptors and helical cytokines. Immunol Today 11:350–354.

    Article  PubMed  CAS  Google Scholar 

  71. Kishimoto T, Akira S, Taga T (1992). Interleukin-6 and its receptor: a paradigm for cytokines. Science 258:593–597.

    Article  PubMed  CAS  Google Scholar 

  72. Yasukawa K, Saito T, Fukunaga T, Sekimori Y, Koishihara Y, Fukui H, Ohsugi Y, Matsuda T, Yawata H, Hirano T, Taga T, Kishimoto T (1990). Purification and characterization of soluble human IL-6 receptor expressed in CHO cells. J Biochem 108:673–676.

    PubMed  CAS  Google Scholar 

  73. Grube BJ, Cochrane CG (1994). Identification of a regulatory domain of the interleukin-6 receptor. J Biol Chem 269:20791–20797.

    PubMed  CAS  Google Scholar 

  74. Yamasaki K, Taga T, Hirata Y, Yawata H, Kawanishi Y, Seed B, Taniguchi T, Hirano T, Kishimoto T (1988). Cloning and expression of the human interleukin-6 (BSF-2/IFN 2) receptor. Science 241:825–828.

    Article  PubMed  CAS  Google Scholar 

  75. Taga T, Hibi M, Hirata Y, Yamasaki K, Yasukawa K, Matsuda T, Hirano T, Kishimoto T (1989). Interleukin-6 triggers the association of its receptor with a possible signal transducer, gpl30. Cell 58:573–581.

    Article  PubMed  CAS  Google Scholar 

  76. Yawata H, Yasukawa K, Natsuka S, Murakami M, Yamasaki K, Hibi M, Taga T, Kishimoto T (1993). Structure-function analysis of human IL-6 receptor: dissociation of amino acid residues required for IL-6 binding and IL-6 signal transduction through gpl30. EMBO J 12:1705–1712.

    PubMed  CAS  Google Scholar 

  77. D’Alessandro F, Colamonici OR, Nordan RP (1993). Direct association of interleukin-6 with a 130-kDa component of the interleukin-6 receptor system. J Biol Chem 268:2149–2153.

    PubMed  Google Scholar 

  78. Narazaki M, Yasukawa K, Saito T, Ohsugi Y, Fukui H, Koishihara Y, Yancopoulos GD, Taga T, Kishimoto T (1993). Soluble forms of the interleukin-6 signal-transducing receptor component gp130 in human serum possessing a potential to inhibit signals through membrane-anchored gpl30. Blood 82:1120–1126.

    PubMed  CAS  Google Scholar 

  79. Taga T, Kishimoto T (1993). Cytokine and receptor signal transduction. FASEB J 7:3387–3396.

    Google Scholar 

  80. Stahl N, Yancopoulos GD (1993). The alphas, betas, and kinases of cytokine receptor complexes. Cell 74:587–590.

    Article  PubMed  CAS  Google Scholar 

  81. Kishimoto T, Taga T, Akira S (1994). Cytokine signal transduction. Cell 76:253–262.

    Article  PubMed  CAS  Google Scholar 

  82. Boulton TG, Stahl N, Yancopoulos GD (1994). Ciliary neurotrophic factor/leukemia inhibitory factor/interleukin 6/oncostatin M family of cytokines induces tyrosine phosphorylation of a common set of proteins overlapping those induced by other cytokines and growth factors. J Biol Chem 269:11648–11655.

    PubMed  CAS  Google Scholar 

  83. Zhong Z, Wen Z, Darnell JE Jr (1994). Stat3: A STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. Science 264: 95–98.

    Article  PubMed  CAS  Google Scholar 

  84. Murakami M, Narazaki M, Hibi M, Yawata H, Yasukawa K, Hamaguchi M, Taga T, Kishimoto T (1991). Critical cytoplasmic region of the IL-6 signal transducer, gpl30, is conserved in the cytokine receptor family. Proc Natl Acad Sci USA 88:11349–11353.

    Article  PubMed  CAS  Google Scholar 

  85. Murakami M, Hibi M, Nakagawa N, Nakagawa T, Yasukawa K, Yamanishi K, Taga T, Kishimoto T (1993). IL-6-induced homodimerization of gpl30 and associated activation of a tyrosine kinase. Science 260:1808–1810.

    Article  PubMed  CAS  Google Scholar 

  86. Ward LD, Howlett GJ, Discolo G, Yasukawa K, Hammacher A, Moritz RL, Simpson RJ (1994). High affinity interleukin-6 receptor is a hexameric complex consisting of two molecules each of interleukin-6, interleukin-6 receptor, and gp-130. J Biol Chem 269:23286–23289.

    PubMed  CAS  Google Scholar 

  87. Stahl N, Boulton TG, Farruggella T, Ip NY, Davis S, Witthuhn B, Quelle FW, Silvennoinen O, Barbieri G, Pellegrini S, Ihle JN, Yancopoulos GD (1994). Association and activation of Jak-Tyk kinases by CNTF-LIF-OSM-IL-6 receptor components. Science 263:92–95.

    Article  PubMed  CAS  Google Scholar 

  88. Lütticken C, Wegenka UM, Yuan J, Buschmann J, Schindler C, Ziemiecki A, Harpur AG, Wilks AF, Yasukawa K, Taga T, Kishimoto T, Barbieri G, Pellegrini S, Sendtner M, Heinrich PC, Horn F (1994). Association of transcription factor APRF and protein kinase Jakl with interleukin-6 signal transducer gpl30. Science 263:89–92.

    Article  PubMed  Google Scholar 

  89. Kumar G, Gupta S, Wang S, Nel AE (1994). Involvement of Janus kinases, p52shc, raf-1, and MEK-1 in the IL-6-induced mitogen-activated protein kinase cascade of a growth-responsive B cell line. J Immunol 153:4436–4447.

    PubMed  CAS  Google Scholar 

  90. Narazaki M, Witthuhn BA, Yoshida K, Silvennoinen O, Yasukawa K, Ihle JN, Kishimoto T, Taga T (1994). Activation of JAK2 kinase mediated by the interleukin 6 signal transducer gpl30. Proc Natl Acad Sci USA 91:2285–2289.

    Article  PubMed  CAS  Google Scholar 

  91. Nakajima T, Kinoshita S, Sasagawa T, Sasaki K, Naruto M, Kishimoto T, Akira S (1993). Phosphorylation at threonine-235 by a ras-dependent mitogen-activated protein kinase cascade is essential for transcription factor NF-IL6. Proc Natl Acad Sci USA 90:2207–2211.

    Article  PubMed  CAS  Google Scholar 

  92. Crews CM, Erikson RL (1993). Extracellular signals and reversible protein phosphorylation: what to mek of it all. Cell 74:215–217.

    Article  PubMed  CAS  Google Scholar 

  93. Nakafuku M, Satoh T, Kaziro Y (1992). Differentiation factors, including nerve growth factor, fibroblast growth factor, and interleukin-6 induce an accumulation of an active Ras/ GTP complex in rat pheochromocytoma PC12 cells. J Biol Chem 267:19448–19454.

    PubMed  CAS  Google Scholar 

  94. Harroch S, Revel M, Chebath J (1994). Interleukin-6 signalling via four transcription factors binding palindromic enhancers of different genes. J Biol Chem 269:26191–26195.

    PubMed  CAS  Google Scholar 

  95. Akira S, Isshiki H, Sugita T, Tanabe O, Kinoshita S, Nishio Y, Nakajima T, Hirano T, Kishimoto T (1990). A nuclear factor for IL-6 expression (NF-IL6) is a member of a C/EBP family. EMBO J 9:1897–1906.

    PubMed  CAS  Google Scholar 

  96. Van Snick J, Cayphas S, Vink A, Uyttenhove C, Coulie P, Simpson R (1986). Purification and NH2-terminal amino acid sequence of a new T cell derived lymphokine with growth factor activity for B cell hybridomas. Proc Natl Acad Sci USA 83:9679–9683.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  98. Corbel C, Melchers F (1984). The synergism of accessory cells and of soluble — factors derived from them in the activation of B cells to proliferation. Immunol Rev 78:51–74.

    Article  PubMed  CAS  Google Scholar 

  99. Walther Z, May LT, Sehgal PB (1988). Transcriptional regulation of the interferon-β2/B cell differentiation factor BSF-2/hepatocyte-stimulating factor gene in human fibroblasts by other cytokines. J Immunol 140:974–977.

    PubMed  CAS  Google Scholar 

  100. Schindler R, Mancilla J, Endres S, Ghorbani R, Clark SC, Dinarello CA (1990). Correlations and interactions in the production of interleukin-6 (IL-6), IL-1, and tumor necrosis factor (TNF) in human blood mononuclear cells: IL-6 suppresses IL-1 and TNF. Blood 75:40–47.

    PubMed  CAS  Google Scholar 

  101. Kohase M, May LT, Tamm I, Vileck J, Sehgal PB (1987). A cytokine network in human diploid fibroblasts: interactions of beta interferons, tumor necrosis factor, platelet-derived growth factor, and interleukin-1. Mol Cell Biol 7:273–280.

    PubMed  CAS  Google Scholar 

  102. Mcintosh JK, Jablons DM, Mulé JJ, Nordan RP, Rudikoff S, Lotze MT, Rosenberg SA (1989). In vivo induction of IL-6 by administration of exogenous cytokines and detection of de novo serum levels of IL-6 in tumor-bearing mice. J Immunol 143:162–167.

    PubMed  CAS  Google Scholar 

  103. Zilberstein A, Ruggieri R, Korn JH, Revel M (1986). Structure and expression of cDNA and genes for human interferon-β2, a distinct species inducible by growth-stimulatory cytokines. EMBO J 5:2529–2537.

    PubMed  CAS  Google Scholar 

  104. Bowcock AM, Kidd JR, Lathrop M, Danshvar L, May LT, Ray A, Sehgal PB, Kidd KK, Cavallisforza LL (1988). The human ‘beta-2 interferon/hepatocyte stimulatory factor/ interleukin-6’ gene: DNA polymorphism studies and localization to chromosome 7p21. Genomics 3:8–16.

    Article  PubMed  CAS  Google Scholar 

  105. Shimizu H, Mitomo K, Watanabe T, Okamoto S, Yamamoto K-I (1990). Involvement of a NF-0438B-like transcription factor in the activation of the interleukin-6 gene by inflammatory lymphokines. Mol Cell Biol 10:561–568.

    PubMed  CAS  Google Scholar 

  106. Isshiki H, Akira S, Tanabe O, Nakajima T, Shimamoto T, Hirano T, Kishimoto T (1990). Constitutive and IL-1 inducible factors interact with the IL-1 responsive element in the IL-6 gene. Mol Cell Biol 10:2757–2764.

    PubMed  CAS  Google Scholar 

  107. Libermann TA, Baltimore D (1990). Activation of interleukin-6 gene expression through the NF-B transcription factor. Mol Cell Biol 10:2327–2334.

    PubMed  CAS  Google Scholar 

  108. Matsusaka T, Fujikawa K, Nishio Y, Mukaida N, Matsushima K, Kishimoto T, Akira S (1993). Transcription factors NF-IL6 and NF-xB synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8. Proc Natl Acad Sci USA 90:10193–10197.

    Article  PubMed  CAS  Google Scholar 

  109. Santhanam U, Ray A, Sehgal PB (1991). Repression of the interleukin 6 gene promoter by p53 and the retinoblastoma susceptibility gene product. Proc Natl Acad Sei USA 88:7605–7609.

    Article  CAS  Google Scholar 

  110. Margulies L, Sehgal PB (1993). Modulation of the human interleukin-6 promoter (IL-6) and transcription factor C/EBP (NF-IL-6) activity by p53 species. J Biol Chem 268:15096–15100.

    PubMed  CAS  Google Scholar 

  111. Thorpe R, Wadhwa M, Bird CR, Mire-Sluis AR (1992). Detection and measurement of cytokines. Blood Rev 6:133–148.

    Article  PubMed  CAS  Google Scholar 

  112. May LT, Viguet H, Kenney JS, Ida N, Allison AC, Sehgal PB (1992). High levels of ‘complexed’ interleukin-6 in human blood. J Biol Chem 267:19698–19704.

    PubMed  CAS  Google Scholar 

  113. Matsuda T, Hirano T, Nagasawa S, Kishimoto T (1989). Identification of α 2-macroglobulin as a carrier protein for IL-6. J Immunol 142:148–152.

    PubMed  CAS  Google Scholar 

  114. Montero-Julian FA, Liautard J, Flavetta S, Romagné F, Gaillard JP, Brochier J, Klein B, Brailly H (1994). Immunoassay for functional human soluble interleukin-6 receptor in plasma based on ligand/receptor interactions. J Immunol Methods 169:111–121.

    Article  PubMed  CAS  Google Scholar 

  115. De Benedetti F, Massa M, Pignatti P, Albani S, Novick D, Martini A (1994). Serum soluble interleukin 6 (IL-6) receptor and IL-6/soluble IL-6 receptor complex in systemic juvenile rheumatoid arthritis. J Clin Invest 93:2114–2119.

    Article  PubMed  Google Scholar 

  116. Arvidson NG, Gudbjörnsson B, Elfman L, Rydén A-C, Tòtterman TH, Hällgren R (1994). Orcadian rhythm of serum interleukin-6 in rheumatoid arthritis. Ann Rheum Dis 53:521–524.

    Article  PubMed  CAS  Google Scholar 

  117. Bauer J, Hohagen F, Ebert T, Timmer J, Ganter U, Krieger S, Lis S, Postler E, Voderholzer U, Berger M (1994). Interleukin-6 serum levels in healthy persons correspond to the sleep-wake cycle. Clin Investig 72:315.

    Article  PubMed  CAS  Google Scholar 

  118. Seiler W, Müller H, Hiemke C (1994). Interleukin-6 in plasma collected with an indwelling cannula reflects local, not systemic, concentrations. Clin Chem 40:1778–1779.

    PubMed  CAS  Google Scholar 

  119. Thavasu PW, Longhurst S, Joel SP, Slevin ML, Balkwill FR (1992). Measuring cytokine levels in blood — importance of anticoagulants, processing, and storage conditions. J Immunol Methods 153:115–124.

    Article  PubMed  CAS  Google Scholar 

  120. Riches P, Gooding R, Millar BC, Rowbottom AW (1992). Influence of collection and separation of blood samples on plasma IL-1, IL-6 and TNF-a concentrations. J Immunol Methods 153:125–131.

    Article  PubMed  CAS  Google Scholar 

  121. Gobbi PG, Cavalli C, Gendarini A, Crema A, Ricevuti G, Federico M, Di Prisco U, Ascari E (1985). Re-evaluation of prognostic significance of symptoms in Hodgkin’s disease. Cancer 56:2874–2880.

    Article  PubMed  CAS  Google Scholar 

  122. Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M (1971). Report of the committee on Hodgkin’s disease staging classification. Cancer Res 31:1860–1861.

    PubMed  CAS  Google Scholar 

  123. Lister TA, Crowther D, Sutcliffe SB, Glatstein E, Canellos GP, Young RC, Rosenberg SA, Coltman CA, Tubiana M (1989). Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease: Cotswold meeting. J Clin Oncol 7:1630–1636.

    PubMed  CAS  Google Scholar 

  124. Longo DL, DeVita VT, Jaffe ES, Mauch P, Urba WJ (1993). Lymphocytic lymphomas. In DeVita VT Jr, Hellman S, Rosenberg SA (eds), Cancer: Principles and Practice of Oncology. JB Lippincott Company: Philadelphia, pp. 1859–1927.

    Google Scholar 

  125. Specht L (1991). Prognostic factors in Hodgkin’s disease. Cancer Treat Rev 18:21–53.

    Article  PubMed  CAS  Google Scholar 

  126. Rodriguez J, Cabanillas F, McLaughlin P, Swan F, Rodriguez M, Hagemeister F, Romaguera J (1992). A proposal for a simple staging system for intermediate grade lymphoma and immunoblastic lymphoma based on the ‘tumor score.’ Ann Oncol 3:711–717.

    PubMed  CAS  Google Scholar 

  127. The International Non-Hodgkin’s Lymphoma Prognostic Factor Project (1993). A predictive model for aggressive non-Hodgkin’s lymphoma. J Engl J Med 329:987–994.

    Article  Google Scholar 

  128. Stasi R, Conforti M, Del Poeta G, Domenica M, Simone D, Coppetelli U, Tribalto M, Cantonetti M, Perrotti A, Venditti A, Papa G (1992). Soluble factors levels in the initial staging of high-grade non-Hodgkin’s lymphomas. Haematologica 77:518–521.

    PubMed  CAS  Google Scholar 

  129. Kurzrock R, Redman J, Cabanillas F, Jones D, Rothberg J, Talpaz M (1993). Serum interleukin 6 levels are elevated in lymphoma patients and correlate with survival in advanced Hodgkin’s disease and with B symptoms. Cancer Res 53:2118–2122.

    PubMed  CAS  Google Scholar 

  130. Stasi R, Stipa E, Masi M, Oliva F, Sciarra A, Perrotti A, Zaccari G, Papa G (1993). Antiphospholipid antibodies: prevalence, clinical significance and correlation to cytokine levels in acute myeloid leukemia and non-Hodgkin’s lymphoma. Thromb Haemostas 70:568–572.

    CAS  Google Scholar 

  131. Stasi R, Veneditti A, Del Poeta G, Conforti M, Coppetelli U, Tribalto M, Papa G (1994). Increased levels of circulating interleukin-6 in patients with newly-diagnosed non-Hodgkin’s lymphoma. Am J Hematol 46:160–161.

    Article  PubMed  CAS  Google Scholar 

  132. Nachbaur DM, Herold M, Maneschg A, Huber H (1991). Serum levels of interleukin-6 in multiple myeloma and other hematologic disorders: correlation with disease activity and other prognostic parameters. Ann Hematol 62:54–58.

    Article  PubMed  CAS  Google Scholar 

  133. Yee C, Sutcliffe S, Messner HA, Minden MD (1992). Interleukin-6 levels in the plasma of patients with lymphoma. Leuk Lymph 7:123–129.

    Article  CAS  Google Scholar 

  134. Seymour JF, Talpaz M, Cabanillas F, Wetzler M, Kurzrock R (1995). Serum interleukin-6 levels correlate with prognosis in diffuse large cell lymphoma. J Clin Oncol 13:575–582.

    PubMed  CAS  Google Scholar 

  135. Gause A, Scholz R, Klein S, Jung W, Diehl V, Tesch H, Hasenclever D, Pfreundschuh M (1991). Increased levels of circulating interleukin-6 in patients with Hodgkin’s disease. Hematol Oncol 9:307–313.

    Article  PubMed  CAS  Google Scholar 

  136. Gause A, Keymis S, Scholz R, Schobert I, Jung W, Diehl V, Pohl C, Pfreundschuh M (1991). Increased levels of circulating cytokines in patients with untreated Hodgkin’s disease. Lymphokine Cytokine Res 11:109–113.

    Google Scholar 

  137. Gause A, Jung W, Keymis S, Schobert I, Scholz R, Schmits R, Diehl V, Pohl C, Hasenclever D, Pfreundschuh M (1992). The clinical significance of cytokines and soluble forms of membrane-derived activation antigens in the serum of patients with Hodgkin’s disease. Leuk Lymph 7:439–447.

    Article  CAS  Google Scholar 

  138. Blay J-Y, Farcet J-P, Lavaud A, Radoux D, Chouaïb S (1994). Serum concentrations of cytokines in patients with Hodgkin’s disease. Eur J Cancer 30A:321–324.

    Article  PubMed  CAS  Google Scholar 

  139. Seymour JF, Talpaz M, Hagemeister FB, Cabanillas F, Kurzrock R (1994). Clinical correlates of elevated interleukin-6 (IL-6) levels in patients (pts) with untreated Hodgkin’s disease (HD). Proc Am Soc Clin Oncol 13:390 (abstr. 1329)

    Google Scholar 

  140. Pizzolo G, Chilosi M, Vinante F, Dazzi F, Lestani M, Perona G, Benedetti F, Todeschini G, Vincenzi C, Trentin L, Semenzato G (1987). Soluble interleukin-2 receptors in the serum of patients with Hodgkin’s disease. Br J Cancer 55:427–428.

    Article  PubMed  CAS  Google Scholar 

  141. Pui C-H, Ip SH, Thompson E, Willimas J, Brown M, Dodge RK, Alberto de Hoyos R, Berard CW, Crist WM (1989). High serum interleukin-2 receptor levels correlate with a poor prognosis in children with Hodgkin’s disease. Leukemia 3:481–484.

    PubMed  CAS  Google Scholar 

  142. Gause A, Pohl C, Tschiersch A, Da Costa L, Jung W, Diehl V, Hasenclever D, Pfreundschuh M (1991). Clinical significance of soluble CD30 antigen in the sera of patients with untreated Hodgkin’s disease. Blood 77:1983–1988.

    PubMed  CAS  Google Scholar 

  143. Pizzolo G, Nadali G, Vinante F, Chilosi M, Perona G (1994). Serum levels of soluble CD30 are elevated in the majority of untreated patients with Hodgkin’s disease and correlate with clinical features and prognosis. Proc Int Soc Haematol 25:205 (abstr. 81).

    Google Scholar 

  144. Nadali G, Vinante F, Ambrosetti A, Todeschini G, Veneri D, Zanotti R, Meneghini V, Ricetti MM, Benedetti F, Vassanelli A, Perona G, Chilosi M, Menestrina F, Fiacchini M, Stein H, Pizzolo G (1994). Serum levels of soluble CD30 are elevated in the majority of untreated patients with Hodgkin’s disease and correlate with clinical features and prognosis. J Clin Oncol 12:793–797.

    PubMed  CAS  Google Scholar 

  145. Falini B, Flenghi L, Fedeli L, Broe MK, Bonino C, Stein H, Dürkop H, Bigerna B, Barbabietola G, Venturi S, Aversa F, Pizzolo G, Bartoli A, Pileri S, Sabattini E, Palumbo R, Martelli MF (1992). In vivo targetting of Hodgkin and Reed-Sternberg cells of Hodgkin’s disease with monoclonal antibody Ber-H2 (CD30): immunohistological evidence. Br J Haematol 82:38–45.

    Article  PubMed  CAS  Google Scholar 

  146. Falini B, Bolognesi A, Flenghi L, Tazzari PL, Broe MK, Stein H, Dürkop H, Aversa F, Corneli P, Pizzolo G, Barbabietola G, Sabattini E, Pileri S, Martelli MF, Stirpe F (1992). Response of refractory Hodgkin’s disease to monoclonal anti-CD30 immunotoxin. Lancet 339:1195–1196.

    Article  PubMed  CAS  Google Scholar 

  147. Miale JB (1977). Laboratory Medicine: Hematology, 5th ed. Mosby: Saint Louis.

    Google Scholar 

  148. Mackiewicz A, Schooltink H, Heinrich PC, Rose-John S (1992). Complex of soluble human IL-6-receptor/IL-6 up-regulates expression of acute-phase proteins. J Immunol 149:2021–2027.

    Google Scholar 

  149. Fattori E, Delia Rocca C, Costa P, Giorgio M, Dente B, Pozzi L, Ciliberto G (1994). Development of progressive kidney damage and myeloma kidney in interleukin-6 transgenic mice. Blood 83:2570–2579.

    PubMed  CAS  Google Scholar 

  150. Hsu S-M, Waldron JA, Xie S-S, Barlogie B (1993). Expression of interleukin-6 in Castleman’s disease. Hum Pathol 24:833–839.

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  152. 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.

    Article  PubMed  CAS  Google Scholar 

  153. May LT, Helfgott DC, Sehgal PB (1986). Anti-ß-interferon antibodies inhibit the increased expression of HLA-B7 mRNA in tumor necrosis factor-treated human fibroblasts: structural studies of the β2 interferon involved. Proc Natl Acad Sci USA 83:8957–8961.

    Article  PubMed  CAS  Google Scholar 

  154. Dansky-Ullmann C, Schlom J, Greiner JW (1933). In vivo regulation of carcinoembryonic antigen (CEA) and class I HLA expression in human colon xenografts by interleukin-6 (IL-6) and the possible role of intrinsic interferon-induction. Proc Am Assoc Cancer Res 34:454 (abstr. 2710).

    Google Scholar 

  155. Kurzrock R, Quesada JR, Talpaz M, Hersh EM, Reuben JM, Sherwin SA, Gutterman JU (1986). Phase I study of multiple dose intramuscularly administered recombinant gamma interferon. J Clin Oncol 4:1101–1109.

    PubMed  CAS  Google Scholar 

  156. Chen YL, Le Vraux V, Leneveu A, Dreyfus F, Stheneur A, Florentin I, De Souusa M, Giroud JP, Flouvat B, Chauvelot-Moachhon L (1994). Acute-phase response, interleukin-6, and alteration of cyclosporine pharmacokinetics. Clin Pharmacol Ther 55:649–660.

    Article  PubMed  CAS  Google Scholar 

  157. Morgan ET, Thomas KB, Swanson R, Vales T, Hwang J, Wright K (1994). Selective suppression of cytochrome P-450 gene expression by interleukins 1 and 6 in rat liver. Biochim Biophys Acta 1219:475–483.

    PubMed  CAS  Google Scholar 

  158. Abdel-Razzak Z, Loyer P, Fautrel A, Gautier J-C, Corcos L, Turlin B, Beaune P, Guillouzo A (1993). Cytokines down-regulate expression of major cytochrome P-450 enzymes in adult human hepatocytes in primary culture. Mol Pharmacol 44:707–715.

    PubMed  CAS  Google Scholar 

  159. Fukuda Y, Sassa S (1994). Suppression of cytochrome P450IA1 by interleukin-6 in human HepG2 hepatoma cells. Biochem Pharmacol 47:1187–1195.

    Article  PubMed  CAS  Google Scholar 

  160. Seymour JF, Talpaz M, Cabanillas F, Wetzler M, Kurzrock R (1993). Clinical correlates and prognostic significance of interleukin-6 (IL-6) levels at diagnosis in patients (pts) with diffuse large cell lymphoma (DLCL). Blood 82 (Suppl l).T35a (abstr. 526).

    Google Scholar 

  161. Kronbach T, Fischer V, Meyer UA (1988). Cyclosporine metabolism in human liver: identification of cytochrome P-450III gene family as the major cyclosporine-metabolising enzyme explains interactions of cyclosporine with other drugs. Clin Pharmacol Ther 43:630–635.

    Article  PubMed  CAS  Google Scholar 

  162. Perry MC (1992). The Chemotherapy Sourcebook. Williams and Wilkins: Baltimore.

    Google Scholar 

  163. Combates NJ, Rzepka RW, Chen Y-NP, Cohen D (1994). NF-IL6, a member of the C/EBP family of transcription factors, binds and trans-activates the human MDR1 gene promoter. J Biol Chem 269:29715–29719.

    PubMed  CAS  Google Scholar 

  164. McClean S, Hill BT (1992). An overview of membrane, cytosolic and nuclear proteins associated with the expression of resistance to multiple drugs in vitro. Biochim Biophys Acta 1114:107–127.

    PubMed  CAS  Google Scholar 

  165. Deuchars KL, Ling V (1989). P-glycoprotein and multidrug resistance in cancer chemotherapy. Semin Oncol 16:156–165.

    PubMed  CAS  Google Scholar 

  166. Reizenstein P (1993). Resistance modifying agents are active in some patients with hematologic malignancy. Leuk Res 17:295–298.

    Article  PubMed  CAS  Google Scholar 

  167. Gottesman MM, Pastan I (1989). Clinical trials of agents that reverse multidrug resistance. J Clin Oncol 7:409–411.

    PubMed  CAS  Google Scholar 

  168. Yuen AR, Sikic BI (1994). Multidrug resistance in lymphomas. J Clin Oncol 12:2453–2459.

    PubMed  CAS  Google Scholar 

  169. Cornelissen JJ, Sonneveld P, Schoester M, Raijmakers HGP, Nieuwenhuis HK, Dekker AW, Lokhorst HM (1994). MDR-1 expression and response to vincristine, doxorubicin, and dexamethasone chemotherapy in multiple myeloma refractory to alkylating agents. J Clin Oncol 12:115–119.

    PubMed  CAS  Google Scholar 

  170. Campos L, Guyotat D, Archimbaud E, Calmard-Orial P, Tsuruo T, Troncy J, Treille D, Fiere D (1992). Clinical significance of multidrug resistance P-glycoprotein expression on acute nonlymphoblastic leukemia cells at diagnosis. Blood 79:473–476.

    PubMed  CAS  Google Scholar 

  171. Zöchbauer S, Gsuur A, Brunner R, Kyrie PA, Lechner K, Pirker R (1994). P-glycoprotein expression as unfavorable prognostic factor in acute myeloid leukemia. Leukemia 8:974–977.

    PubMed  Google Scholar 

  172. Yee C, Biondi A, Wang XH, Iscove NN, de Sousa J, Aarden LA, Wong GG, Clark SC, Messner HA, Minden MD (1989). A possible autocrine role for interleukin-6 in two lymphoma cell lines. Blood 74:798–804.

    PubMed  CAS  Google Scholar 

  173. Shimizu S, Hirano T, Yoshioka R, Sugai S, Matsuda T, Taga T, Kishimoto T, Konda S (1988). Interleukin-6 (B-cell stimulatory factor-2)-dependent growth of a Lennert’s lymphoma-derived T-cell line (KT-3). Blood 72:1826–1828.

    PubMed  CAS  Google Scholar 

  174. Chang H, Jamal N, Wang X-H, Minden MD, Messner HA (1992). Constitutive production of the interleukins IL-5 and IL-6 by the lymphoma cell line OCI-Ly 17 derived from a patient with malignant lymphoma and hypereosinophilia. Leuk Lymph 8:97–107.

    Article  CAS  Google Scholar 

  175. Lavabre-Bertrand T, Exbrayat C, Liotard J, Bourquard P, Duperray C, Gaillard JP, Rossi JF, Navarro M, Brochier J (1994). Detection of membrane and soluble interleukin-6 receptor in chronic lymphoid malignancies. Proc Int Soc Haematol 25:321 (abstr. 538).

    Google Scholar 

  176. Woodroofe C, Muller W, Rutther U (1992). Long-term consequences of interleukin-6 overexpression in transgeneic mice. DNA Cell Biol 11:587–592.

    Article  PubMed  CAS  Google Scholar 

  177. Suematsu S, Matsusaka T, Matsuda T, Ohno S, Miyazaki J-I, Yamamura K-I, Hirano T, Kishimoto T (1992). Generation of plasmacytomas with the chromosomal translocation t(12;15) in interleukin 6 transgenic mice. Proc Natl Acad Sei USA 89:232–235.

    Article  CAS  Google Scholar 

  178. Durandy A, Emilie D, Peuchmaur M, Forveille M, Clement C, Wijdenes J, Fischer A (1994). Role of IL-6 in promoting growth of human EBV-induced B-cell tumors in severe combined immunodeficient mice. J Immunol 152:5361–5367.

    PubMed  CAS  Google Scholar 

  179. Scala G, Quinto I, Ruocco MR, Arcucci A, Mallardo M, Caretto P, Forni G, Venuta S (1990). Expression of an exogenous interleukin 6 gene in human Epstein Barr virus B cell confers growth advantage and in vivo tumorigenicity. J Exp Med 172:61–68.

    Article  PubMed  CAS  Google Scholar 

  180. Tanner J, Tosato G (1991). Impairment of natural killer functions by interleukin 6 increases lymphoblastoid cell tumorigenicity in athymic mice. J Clin Invest 88:239–247.

    Article  PubMed  CAS  Google Scholar 

  181. 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.

    PubMed  CAS  Google Scholar 

  182. Uchiyama H, Barut BA, Mohrbacher AF, Chauhan D, Anderson KC (1993). Adhesion of human myeloma-derived cell lines to bone marrow stromal cells stimulates interleukin-6 secretion. Blood 82:3712–3720.

    PubMed  CAS  Google Scholar 

  183. Tosato G, Tanner G, Jones KD, Revel M, Pike SE (1990). Identification of IL-6 as an autocrine growth factor for Epstein-Barr virus-immortalized cells. J Virol 64:3033–3047.

    PubMed  CAS  Google Scholar 

  184. Ni K, O’Neill HC (1992). Proliferation of the BCL1 B cell lymphoma induced by IL-4 and IL-5 is dependent on IL-6 and GM-CSF. Immunol Cell Biol 70:315–322.

    Article  PubMed  CAS  Google Scholar 

  185. Levy Y, Tsapis A, Brouet J-C (1991). Interleukin-6 antisense oligonucleotides inhibit the growth of human myeloma cells. J Clin Invest 88:696–699.

    Article  PubMed  CAS  Google Scholar 

  186. Barut B, Chauhan D, Uchiyama H, Anderson KC (1993). Interleukin-6 functions as an intacellular growth factor in hairy cell leukemia in vitro. J Clin Invest 92:2346–2352.

    Article  PubMed  CAS  Google Scholar 

  187. Young L, Alifieri C, Hennessy K, Evans H, O’Hara C, Anderson KC, Ritz J, Shapiro RS, Rickinson A, Kieff E, Cohen JI (1989). Expression of Epstein-Barr virus transformation-associated genes in tissues of patients with EBV lymphoproliferative disease. N Engl J Med 321:1080–1085.

    Article  PubMed  CAS  Google Scholar 

  188. Shapiro RS (1990). Epstein-Barr virus-associated B-cell lymphoproliferative disorders in immunodeficiency: meeting the challenge. J Clin Oncol 8:371–373.

    PubMed  CAS  Google Scholar 

  189. Feuer G, Chen ISY (1992). Mechanisms of human T-cell leukemia virus-induced leukemogenesis. Biochim Biophys Acta 1114:223–233.

    PubMed  CAS  Google Scholar 

  190. Mori N, Shirakawa F, Shimizu H, Murakami S, Oda S, Yamamoto K-I, Eto S (1994). Transcriptional regulation of the human interleukin-6 gene promoter in human T-cell leukemia virus type-1-infected cell lines: evidence for the involvement of NF-xB. Blood 84:2904–2911.

    PubMed  CAS  Google Scholar 

  191. Lal RB, Rudolph D, Buckner C, Pardi D, Hooper WC (1993). Infection with human T-lymphotrophic viruses leads to constitutive expression of leukemia inhibitory factor and interleukin-6. Blood 81:1827–1832.

    PubMed  CAS  Google Scholar 

  192. Hsu S-M, Xie S-S, Waldron JA Jr (1992). Functional heterogeneity and pathogenic significance of interleukin-6 in B-cell lymphomas. Am J Pathol 141:915–923.

    PubMed  CAS  Google Scholar 

  193. Emilie D, Coumbaras J, Raphael M, Devergne O, Delecluse HJ, Gisselbreacht C, Michiels JF, Van Damme J, Taga T, Kishimoto T, Crevon MC, Galanaud P (1992). Interleukin-6 production in high-grade B-cell lymphomas: correlation with the presence of malignant immunoblasts in acquired immunodeficiency syndrome and in human immunodeficieny virus-seronegative patients. Blood 80:498–504.

    PubMed  CAS  Google Scholar 

  194. Jücker M, Abts H, Li W, Schindler R, Merz H, Günther A, von Kalle C, Schadt M, Diamantstein T, Feller AC, Krueger GRF, Diehl V, Blankenstein T, Tesch H (1991). Expression of interleukin-6 and interleukin-6 receptor in Hodgkin’s disease. Blood 77:2413–2418.

    PubMed  Google Scholar 

  195. Takeshita M, Sumiyoshi Y, Masuda Y, Ohshima K, Yoshida T, Kikuchi M, Müller H (1993). Cytokine (interleukin-1 alpha, interleukin-1 beta, tumor necrosis factor alpha, and interleukin-6)-possessing cells in lymph nodes of malignant lymphoma. Pathol Res Pract 189:18–25.

    PubMed  CAS  Google Scholar 

  196. Klein S, Jücker M, Diehl V, Tesch H (1992). Production of multiple cytokines by Hodgkin’s disease derived cell lines. Hematol Oncol 10:319–329.

    Article  PubMed  CAS  Google Scholar 

  197. Tesch H, Jücker M, Klein S, Abts H, Günther A, Krueger GRF, Diehl V (1992). Hodgkin and Reed-Sternberg cells express interleukin 6 and interleukin 6 receptors. Leuk Lymph 7:297–303.

    Article  CAS  Google Scholar 

  198. Hsu S-M, Xie S-S, Hsu P-L, Waldron JA Jr (1992). Interleukin-6, but not interleukin-4, is expressed by Reed-Sternberg cells in Hodgkin’s disease with or without histologic features of Castleman’s disease. Am J Pathol 141:129–138.

    PubMed  CAS  Google Scholar 

  199. Perfetti V, Dragani TA, Paulli M, Castelli G, Bellotti V, Gobbi PG, Merlini G (1992). Gene expression of pyrogenic cytokines in Hodgkin’s disease lymph nodes. Haematologica 77:221–225.

    PubMed  CAS  Google Scholar 

  200. Foss H-D, Herbst H, Oelmann E, Samol J, Grebe M, Blankenstein T, Matthes J, Qin Z-H, Falini B, Pileri S, Diamantstein T, Stein H (1993). Lymphotoxin, tumor necrosis factor and interleukin-6 gene transcripts are present in Hodgkin and Reed-Sternberg cells of most Hodgkin’s disease cases. Br J Haematol 84:627–635.

    Article  PubMed  CAS  Google Scholar 

  201. Müller H, Takeshita M, Krause J, Schuster K, Kikuchi M, Stutte HJ (1992). Immunohis-tochemical in situ demonstration of cytokines in Hodgkin and non-Hodgkin lymphoma. Verh Dtsch Ges Pathol 76:164–168.

    PubMed  Google Scholar 

  202. Hussell T, Isaacson PG, Spencer J (1993). Proliferation and differentiation of tumour cells from B-cell lymphoma of mucosa-associated lymphoid tissue in vitro. J Pathol 169:221–227.

    Article  PubMed  CAS  Google Scholar 

  203. Tosato G, Jones K, Breinig MK, McWilliams HP, McKnight JLC (1993). Interleukin-6 production in post-transplant lymphoproliferative disease. J Clin Invest 91:2806–2814.

    Article  PubMed  CAS  Google Scholar 

  204. Pluda JM, Venzon DJ, Tosato G, Lietzau J, Wyvill K, Nelson DL, Jaffe ES, Karp JE, Broder S, Yarchoan R (1993). Parameters affecting the development of non-Hodgkin’s lymphoma in patients with severe human immunodeficiency virus infection receiving antiretroviral therapy. J Clin Oncol 11:1099–1107.

    PubMed  CAS  Google Scholar 

  205. Levine AM (1992). Acquired immunodeficiency syndrome-related lymphoma. Blood 80: 8–20.

    PubMed  CAS  Google Scholar 

  206. Tanner JE, Menezes J (1994). Interleukin-6 and Epstein-Barr virus induction by cyclosporine A: potential role in lymphoproliferative disease. Blood 84:3956–3964.

    PubMed  CAS  Google Scholar 

  207. Cabanillas F, Rodriguez MA, Swan F Jr (1990). Recent trends in the management of lymphomas at M. D. Anderson Cancer Center. Semin Oncol 6 (Suppl 10):28–33.

    Google Scholar 

  208. Chen L, Mory Y, Zilberstein A, Revel M (1988). Growth inhibition of human breast carcinoma and leuukemia/lymphoma cell lines by recombinant interferon-β2. Proc Natl Acad Sci USA 85:8037–8041.

    Article  PubMed  CAS  Google Scholar 

  209. Mule JJ, McKintosh JK, Jablongs DM, Rosenberg SA (1990). Antitumor activity of recombinant interleukin-6 in mice. J Exp Med 171:629–636.

    Article  PubMed  CAS  Google Scholar 

  210. Eisenthal A, Kashtan H, Rabau M, Ramakrishna V, Chaitchik S, Skornick Y (1993). Antitumor effects of recombinant interleukin-6 expressed in eukaryotic cells. Cancer Immunol Immunother 36:101–107.

    Article  PubMed  CAS  Google Scholar 

  211. Bataille R, Jourdan M, Zhang X-G, Klein B (1989). Serum levels of interleukin 6, a potent myeloma cell growth factor, as a reflect of disease severity in plasma cell dyscrasias. J Clin Invest 84:2008–2011.

    Article  PubMed  CAS  Google Scholar 

  212. Ludwig H, Nachbaur D, Fritz E, Krainer M, Huber H (1991). Interleukin-6 is a prognostic factor in multiple myeloma. Blood 77:2794–2795.

    PubMed  CAS  Google Scholar 

  213. Blay J-Y, Negrier S, Combaret V, Attali S, Goillot E, Merrouche Y, Mercatello A, Ravault A, Tourani J-M, Moskovtchenko J-F, Philip T, Favrot M (1992). Serum level of interleukin 6 as a prognosis factor in metastatic renal cell carcinoma. Cancer Res 52:3317–3322.

    PubMed  CAS  Google Scholar 

  214. Scambia G, Testa U, Panici PB, Foti E, Martucci R, Gadducci A, Perillo A, Facchini V, Peschle C, Mancusco S (1995). Prognostic significance of interleukin 6 serum levels in patients with ovarian cancer. Br J Cancer 71:354–356.

    Article  PubMed  CAS  Google Scholar 

  215. Tartour E, Dorval T, Mosseri V, Deneux L, Mathiot C, Brailly H, Montero F, Joyeux I, Pouillart P, Fridman WH (1994). Serum interleukin 6 amnd C-reactive protein levels correlate with resistance to IL-2 therapy and poor survival in melanoma patients. Br J Cancer 69:911–913.

    Article  PubMed  CAS  Google Scholar 

  216. Ravoet C, De Grève J, Vandewoude K, Kerger J, Sculier J-P, Lacor P, Stryckmans P, Piccart M (1994). Tumor stimulating effects of recombinant human interleukin-6. Lancet 344:1576–1577.

    Article  PubMed  CAS  Google Scholar 

  217. Friedman S, Henry-Amar M, Cosset J-M, Carde P, Hayat M, Dupouy N, Tubiana M (1988). Evolution of erythrocyte sedimentation rate as predictor of early relapse in posttherapy early-stage Hodgkin’s disease. J Clin Oncol 6:596–602.

    PubMed  CAS  Google Scholar 

  218. Dimopoulos MA, Cabanillas F, Lee JJ, Swan F, Fuller L, Allen PK, Hagemeister FB (1993). Prognostic role of serum β2-microglobulin in Hodgkin’s disease. J Clin Oncol 11:1108–1111.

    PubMed  CAS  Google Scholar 

  219. Swan F Jr, Velasquez WS, Tucker S, Redman JR, Rodriguez MA, McLaughlin P, Hagemeister FB, Cabanillas F (1989). A new serologic staging system for large-cell lymphomas based on initial β2-microglobulin and lactate dehydrogenase levels. J Clin Oncol 7:1518–1527.

    PubMed  Google Scholar 

  220. Johnson PWM, Whelan J, Longhurst S, Stepiewska, Matthews J, Amess J, Norton A, Rohatiner AZS, Lister TA (1993). β2-microglobulin: a prognostic factor in diffuse aggressive non-Hodgkin’s lymphomas. Br J Cancer 67:792–797.

    Article  PubMed  CAS  Google Scholar 

  221. Savino R, Ciapponi L, Lahm A, Demartis A, Cabibbo A, Toniatti C, Delmastro P, Altamura 5, Ciliberto G (1994). Rational design of a receptor super-antagonist of human interleukin-6. EMBO J 13:5863–5870.

    PubMed  CAS  Google Scholar 

  222. Schwabe M, Brini AT, Bosco MC, Rubboli F, Egawa M, Zhao J, Princier GL, Kung H-f (1994). Disruption by interferon-α of an autocrine interleukin-6 growth loop in IL-6-dependent U266 myeloma cells by homologous and heterologous down-regulation of the IL-6 receptor α- and β-chains. J Clin Invest 94:2317–2325.

    Article  PubMed  CAS  Google Scholar 

  223. Portier M, Zhang X-G, Caron E, Lu Z-Y, Bataille R, Klein B (1993). 03B3-interferon in multiple myeloma: inhibition of interleukin-6 (IL-6)-dependent myeloma cell growth and downregulation of IL-6-receptor expression in vitro. Blood 81:3076–3082.

    PubMed  CAS  Google Scholar 

  224. McLaughlin P, Cabanillas F, Hagemeister FB, Swan F Jr, Romaguera JE, Taylor S, Rodriguez MA, Velasquez WS, Redman JR, Gutterman JU (1993). CHOP-Bleo plus interferon for stage IV low-grade lymphoma. Ann Oncol 4:205–211.

    PubMed  CAS  Google Scholar 

  225. Smalley RV, Andersen JW, Hawkins MJ, Bhide V, O’Connell MJ, Oken MM, Borden EC (1992). Interferon alfa combined with cytotoxic chemotherapy for patients with non-Hodgkin’s lymphoma. N Engl J Med 327:1336–1341.

    Article  PubMed  CAS  Google Scholar 

  226. Avilés A, Díaz-Maqueo JC, García EL, Talavera A, Guzmán R (1992). Maintenance therapy with interferon alfa 2b in patients with diffuse large cell lymphoma. Invest New Drugs 10:351–355.

    Article  PubMed  Google Scholar 

  227. Suzuki H, Yasukawa K, Saito T, Goitsuka R, Hasegawa A, Ohsugi Y, Taga T, Kishimoto T (1992). Anti-human interleukin-6 receptor antibody inhibits human myeloma growth in vivo. Eur J Immunol 22:1989–1993.

    Article  PubMed  CAS  Google Scholar 

  228. Brakenhoff JPJ, de Hon FD, Fontaines V, ten Boekel E, Schooltink H, Rose-John S, Heinrich PC, Content J, Aarden LA (1994). Development of a human interleukin-6 receptor antagonist. J Biol Chem 269:86–93.

    Google Scholar 

  229. de Hon FD, Ehlers M, Rose-John S, Ebeling SB, Bos HK, Aarden LA, Brakenhoff JPJ (1994). Development of an interleukin (IL) 6 receptor antagonist that inhibits Independent growth of human myeloma cells. J Exp Med 180:2395–2400.

    Article  PubMed  Google Scholar 

  230. Kreitman R, Siegall CB, Fitzgerald DJP, Epstein J, Barlogie B, Pastan I (1992). Interleukin-6 fused to a mutant form of Pseudomonas exotoxin kills malignant cells from patients with multiple myeloma. Blood 79:1775–1780.

    PubMed  CAS  Google Scholar 

  231. Mahieu M, Deschuyteneer R, Forget D, Vandenbussche P, Content J (1994). Construction of a ribozyme directed against human interleukin-6 mRNA: evaluation of its catalytic activity in vitro and in vivo. Blood 84:3758–3765.

    PubMed  CAS  Google Scholar 

  232. Cohen JS (1991). Biochemical therapy: antisense compounds. In DeVita VT Jr, Hellman S, Rosenberg SA (eds), Biologic Therapy of Cancer. Lippincott: Philadelphia, pp. 763–775.

    Google Scholar 

Download references

Authors
  1. John F. Seymour
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Razelle Kurzrock
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Hematology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Doulevard, Box 55, Houston, TX, 77030, USA

    Emil J. Freireich M.D.

  2. Department of Hematology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 61, Houston, TX, 77030, USA

    Hagop Kantarjian M.D.

Rights and permissions

Reprints and permissions

Copyright information

© 1996 Kluwer Academic Publishers, Boston

About this chapter

Cite this chapter

Seymour, J.F., Kurzrock, R. (1996). Interleukin-6: biologic properties and role in lymphoproliferative disorders. In: Freireich, E.J., Kantarjian, H. (eds) Molecular Genetics and Therapy of Leukemia. Cancer Treatment and Research, vol 84. Springer, Boston, MA. https://doi.org/10.1007/978-1-4613-1261-1_9

Download citation

  • DOI: https://doi.org/10.1007/978-1-4613-1261-1_9

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4612-8537-3

  • Online ISBN: 978-1-4613-1261-1

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation