, Volume 2, Issue 4, pp 363–373 | Cite as

Interleukin 6 (IL-6)

  • Tadashi Matsuda
  • Toshio Hirano


Public Health 
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  1. 1.
    Muraguchi A, Kishimoto T, Miki Y, Kuritani T, Kaieda T, Yoshizaki K, Yamamura Y. T cell-replacing factor (TRF)induced IgG secretion in human B blastoid cell line and demonstration of acceptors for TRF. J Immunol 1981; 127: 412–6.Google Scholar
  2. 2.
    Teranishi T, Hirano T, Arima N, Onoue K. Human helper T cell factor(s) (ThF). II. Induction of IgG production in B lymphoblastoid cell lines and identification of T cell-replacing factor-(TRF) like factor(s). J Immunol 1982; 128: 1903–8.Google Scholar
  3. 3.
    Hirano T, Taga T, Nakano N, Yasukawa K, Kashiwamura S, Shimizu K, Nakajima K, Pyun K H, Kishimoto T. Purification to homogeneity and characterization of human B cell differentiation factor (BCDF or BSFp-2). Proc Natl Acad Sci USA 1985; 82: 5490–4.Google Scholar
  4. 4.
    Hirano T, Yasukawa K, Harada H, Taga T, Watanabe Y, Matsuda T, Kashiwamura S, Nakajima K, Koyama K, Iwamatsu A, Tsunasawa S, Sakiyama F, Matsui H, Takahara Y, Taniguchi T, Kishimoto T. Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature 1986; 324: 73–6.Google Scholar
  5. 5.
    Kishimoto T, Hirano T. Molecular regulation of B lymphocyte response. Ann Rev Immunol 1988; 6: 485–512.Google Scholar
  6. 6.
    Hirano T, Kishimoto T. Interleukin 6. In: Sporn MB, Roberts AB, eds. Handbook of experimental pharmacology. Peptide growth factors and their receptors. Berlin: Springer-Verlag, 1990; 95: 633–65.Google Scholar
  7. 7.
    Metcalf D. The molecular biology and functions of the granulocyte-macrophage colony-stimulating factors. Blood 1986; 67: 257–67.Google Scholar
  8. 8.
    Ikebuchi K, Wong GG, Clark SC, Ihle JN, Hirai Y, Ogawa M. Interleukin-6 enhancement of interleukin-3-dependent proliferation of multipotential hemopoietic progenitors. Proc Natl Acad Sci USA 1987; 84: 9035–9.Google Scholar
  9. 9.
    Miyaura C, Onozaki K, Akiyama Y, Taniyama T, Hirano T, Kishimoto T, Suda T. Recombinant human interleukin 6 (B-cell stimulatory factor 2) is a potent inducer of differentiation of mouse myeloid leukemia cells (MI). FEBS Lett 1988; 234: 17–21.Google Scholar
  10. 10.
    Ishibashi T, Kimura H, Uchida T, Kariyone S, Friese P, Burstein SA. Human interleukin 6 is a direct promoter of maturation of megakaryocytesin vitro. Proc Natl Acad Sci USA 1989; 86: 5953–7.Google Scholar
  11. 11.
    Takatsuki F, Okano A, Suzuki C, Chieda R, Takahara Y, Hirano T, Kishimoto T, Hamuro J, Akiyama Y. Human recombinant interleukin 6/B cell stimulatory factor 2 (IL-6/BSF-2) augments murine antigenspecific antibody responses in vitro andin vivo. J Immunol 1988; 141: 3072–7.Google Scholar
  12. 12.
    Okano A, Suzuki C, Takatsuki F, Akiyama Y, Koike K, Nakahata T, Hirano T, Kishimoto T, Ozawa K, Asano S. Effects of interleukin-6 on hematopoiesis in bone marrow-transplanted mice. Transplantation 1989; 47: 738–40.Google Scholar
  13. 13.
    Ishibashi T, Kimura H, Shikama Y, Uchida T, Kariyone S, Hirano T, Kishimoto T, Takatsuki F, Akiyama Y. Interleukin 6 is a potent thrombopoietic factorin vivo in mice. Blood 1989; 74: 1241–4.Google Scholar
  14. 14.
    Hirano T, Matsuda T, Turner M, Miyasaka N, Buchan G, Tang B, Sato K, Shimizu M, Maini R, Feldman M, Kishimoto T. Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis. Eur J Immunol 1988; 18: 1797–1801.Google Scholar
  15. 15.
    Horii Y, Muraguchi A, Iwano M, Matsuda T, Hirayama T, Yamada H, Fujii Y, Dohi K, Ishikawa H, Ohmoto Y, Yoshizaki K, Hirano T, Kishimoto T. Involvement of interleukin-6 in mesangial proliferative glomerulonephritis. J Immunol 1989; 143: 3949–55.Google Scholar
  16. 16.
    Kawano M, Hirano T, Matsuda T, Taga T, Horii Y, Iwato K, Asaoku H, Tang B, Tanabe O, Tanaka H, Kuramoto A, Kishimoto T. Autocrine generation and essential requirement of BSF-2/IL-6 for human multiple myelomas. Nature 1988; 332: 83–5.Google Scholar
  17. 17.
    Jambou RC, Snouwaert JN, Bishop GA, Stebbins JR, Frelinger JA, Fowlkes DM. High-level expression of a bioengineered, cystein-free hepatocyte-stimulating factor (interleukin 6)-like protein. Proc Natl Acad Sci USA 1988; 85: 9426–30.Google Scholar
  18. 18.
    Ida N, Sakurai S, Hosaka T, Hosoi K, Kunitomo T, Shimazu T, Maruyama Y, Kahase M. Establishment of strongly neutralizing monoclonal antibody to human interleukin-6 and its epitope analysis. Biochem Biophys Res Commun 1989; 165: 728–34.Google Scholar
  19. 19.
    Yasukawa K, Hirano T, Watanabe Y, Muratani K, Matsuda T, Kishimoto T. Structure and expression of human B cell stimulatory factor 2 (BSF-2/IL-6) gene. EMBO J 1987; 6: 2939–45.Google Scholar
  20. 20.
    Tanabe O, Akira S, Kamiya T, Wong GG, Hirano T, Kishimoto T. Genomic structure of the murine IL-6 gene: high degree conservation of potential regulatory sequences between mouse and human. J Immunol 1988; 41: 3875–81.Google Scholar
  21. 21.
    Sehgal PB, Zilberstein A, Ruggieri R-M, May LT, Ferguson-Smith A, Slate DL, Revel M, Ruddle F. Human chromosome 7 carries theβ 2 interferon gene. Proc Natl Acad Sci USA 1986; 83: 5219–22.Google Scholar
  22. 22.
    Mock BA, Nordan RP, Justice MJ. Kozak C, Jenkins NA, Copeland NG, Clask SC, Wong GG, Rudikoff S. The murine IL-6 gene maps to the proximal region of chromosomes 5. J Immunol 1989; 142: 1372–6.Google Scholar
  23. 23.
    Horii Y, Muratuchi A, Suematu S, Matsuda T, Yoshizaki K, Hirano T, Kishimoto T. Regulation of BSF-2/11-6 production by human mononuclear cells: macrophagedependent synthesis of BSF-2/IL-6 by T cells. J Immunol 1988; 141: 1529–35.Google Scholar
  24. 24.
    Van Snick J, Vink A, Cayphas S, Uyttenhove C. Interleukin-HPI, a T cell-derived hybridoma growth factor that supports thein vitro growth of murine plasmacytomas. J Exp Med 1987; 165: 641–9.Google Scholar
  25. 25.
    Helfgott DC, May LT, Sthoeger Z, Tamm I, Sehgal PB. Bacterial lipopolysaccharide (endotoxin) enhances expression and secretion ofβ 2 interferon by human fibroblasts. J Exp Med 1987; 166: 1300–9.Google Scholar
  26. 26.
    Sehgal PB, Helfgott, DC, Santhanam U, Tatter SB, Clarick RH, Ghrayeb J, May LT. Regulation of the acute phase and immune responses in viral disease. J Exp Med 1988; 167: 1951–6.Google Scholar
  27. 27.
    Frei K, Leist TP, Meager A, Gallo P, Leppert D, Zinkernagel RM, Fontana A. Production of B cell stimulatory factor-2 and interferonγ in the central nervous system during viral meningitis and encephalitis. J Exp Med 1988; 168: 449–53.Google Scholar
  28. 28.
    Nakajima K, Martinez-Maza O, Hirano T, Nishanian P, Salazar-Gonzalez JF, Fahey JL, Kishimoto T, Induction of interleukin 6(BSF-2/IFN-β 2) production by the human immunodeficiency virus (HIV). J Immunol 1989; 142: 144–7.Google Scholar
  29. 29.
    Ray A, Sassone-Corsi P, Shehgal PB. A multiple cytokine-and second messenger-responsive element in the enhancer of the human interleukin-6 gene: similarities with c-fos gene regulation. Mol Cell Biol 1989; 9: 5537–47.Google Scholar
  30. 30.
    Isshiki H, Akira S, Tanabe O, Nakajima T, Shimamoto T, Hirano T, Kishimoto T. Constitutive and IL-1 inducible factors interact with the IL-1 responsive element in the IL-6 gene. Mol Cell Biol, in press.Google Scholar
  31. 31.
    Akira, S., H. Isshiki, T. Sugita, O. Tanabe, S. Kinoshita, Y. Nishio, T. Nakajima, T. Hirano, and T. Kishimoto. A nuclear factor for IL-6 expression (NF-IL-6) is a member of a C/EBP family. EMBO J, in press.Google Scholar
  32. 32.
    Shimizu H, Mitomo K, Watanabe T, Okamoto S, Yamamoto K. Involvement of a NF-κB-Like transcription factor in the activation of the interleukin-6 Gene by inflammatory lymphokines. Mol Cell Biol 1990; 10: 561–8.Google Scholar
  33. 33.
    Taga T, Kawanishi K, Hardy RR, Hirano T, Kishimoto T. Receptors for B cell stimulatory factor 2 (BSF-2): quantitation, specificity, distribution and regulation of the expression. J Exp Med 1987; 166: 967–81.Google Scholar
  34. 34.
    Yamasaki K, Tap T, Hirata Y, Yawata H, Kawanishi Y, Seed B, Taniguchi T, Hirano T, Kishimoto T, Kishimoto T. Cloning and expression of the human interleukin-6 (BSF-2/IFNβ2) receptor. Science 1988; 241: 825–8.Google Scholar
  35. 35.
    Taga T, Hibi M, Hirata Y, Yamasaki K, Yasukawa K, Matsuda T, Hirano T, Kishimoto T. Interleukin 6 (IL-6) triggers the association of its receptor (IL-6-R) with a possible signal transducer, gp130. Cell 1989; 58: 573–81.Google Scholar
  36. 36.
    Hatakeyama M, Tsudo M, Minamoto S, Kono T, Doi T, Miyata T, Miyasaka M, Taniguchi T. Interleukin-2 receptorβ chain gene: generation of three receptor forms by cloned humanα andβ chain cDNA's. Science 1989; 244: 551–6.Google Scholar
  37. 37.
    Itoh N, Yonehara S, Schreurs J, Gorman DM, Maruyama K, Ishii A, Yahara I, Arai K, Miyajima A. Cloning of an interleukin-3 receptor gene: A member of a distinct receptor gene family. Science 1990; 247: 324–7.Google Scholar
  38. 38.
    Mosley B, Beckmann MP, March CJ, Idzerda RL, Gimpel SD, VandenBos T, Friend D, Alpert A, Anderson D, Jackson J, Wigall JM, Smith C, Gallis B, Sims JE, Urdal D, Widmer MB, Cosman D, Park LS. The Murine interleukin-4 receptor: Molecular cloning and characterization of secreted and membrane bound forms. Cell 1989; 59: 335–48.Google Scholar
  39. 39.
    Gearing DP, King JA, Gough NM, Nicola NA. Expression cloning of a receptor for human granulocyte-macrophage colony-stimulating factor. EMBO J 1989; 8: 3667–76.Google Scholar
  40. 40.
    D'Andrea AD, Lodish HF, Wong GG. Expression cloning of the murine erythropoietin receptor. Cell 1989; 57: 277–85.Google Scholar
  41. 41.
    Sugita T, Totsuka T, Saito M, Yamasaki K, Taga T, Hirano T, Kishimoto T. Functional murine IL-6 receptor with the intracistemal A-particle gene product at its cytoplasmic domain: its possible role in plasmacytomagenesis. J Exp Med, in press.Google Scholar
  42. 42.
    Muraguchi A, Hirano T, Tang B, Matsuda T, Horii Y, Nakajima K, Kishimoto T. The essential role of B cell stimulatory factor 2 (BSF-2/IL-6) for the terminal differentiation of B cells. J Exp Med 1988; 67: 332–44.Google Scholar
  43. 43.
    Vink A, Coulie PG, Wauters P, Nordan RP, Van Snick J. B cell growth and differentiation activity of interleukin-HP1 and related murine plasmacytoma growth factors. Synergy with interleukin I. Eur J Immunol 1988; 18: 607–12.Google Scholar
  44. 44.
    Beagley KW, Eldridge JH, Lee F, Kiyono H, Everson MP, Koopman WJ, Hirano T, Kishimoto T, McGhee JR. Interleukins and IgA synthesis: human and murine IL-6 induce high rate IgA secretion in IgA-committed B cells. J Exp Med 1989; 169: 2133–48.Google Scholar
  45. 45.
    Garman RD, Jacobs KA, Clark SC, Raulet DH. 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 1987; 84: 7629–33.Google Scholar
  46. 46.
    Le J, Fredrickson G, Reis LFL, Diamantsein T, Hirano T, Kishimoto T, Vilcek J. Interleukin 2-dependent and interleukin 2-independent pathways of regulation of thymocyte function by interleukin 6. Proc Natl Acad Sci USA 1988; 85: 8643–7.Google Scholar
  47. 47.
    Lotz M, Jirik F, Kabouridis R, Tsoukas C, Hirano T, Kishimoto T, Carson DA. BSF-2/IL-6 is a costimulant for human thymocytes and T lymphocytes. J Exp Med 1988; 167: 1253–8.Google Scholar
  48. 48.
    Takai Y, Wong GG, Clark SC, Burakoff SJ, Herrmann SH. B cell stimulatory factor-2 is involved in the differentiation of cytotoxic T lymphocytes. J Immunol 1988; 140: 508–12.Google Scholar
  49. 49.
    Okada M, Kitahara M, Kishimoto S, Matsuda T, Hirano T, Kishimoto T. BSF-2/IL-6 functions as killer helper factor in thein vitro induction of cytotoxic T cells. J Immunol 1988; 141: 1543–9.Google Scholar
  50. 50.
    Koike K, Nakahata T, Tkai M, Kobayashi T, Ishiguro A, Tsuji K, Naganuma K, Okano A, Akiyama Y, Akabane T. Synergism of BSF-2/interleukin 6 and interleukin 3 on development of multipotential hemopoietic progenitors in serum-free culture. J Exp Med 1988; 168: 879–90.Google Scholar
  51. 51.
    Leary AG, Ikebuchi K, Hirai Y, Wong GG, Yang Y, Clark SC, Ogawa M. Synergism between interleukin-6 and interleukin-3 in supporting proliferation of human hematopoitic stem cells: comparison with interleukin-l-alpha. Blood 1988; 171: 1759–63.Google Scholar
  52. 52.
    Chiu C-P, Moulds C, Coffman RL, Rennick D, Lee F. Multiple biological activities are expressed by a mouse interleukin 6 cDNA clone isolated from bone marrow stromal cells. Proc Natl Acad Sci USA 1988; 85: 7099–103.Google Scholar
  53. 53.
    Okano A, Suzuki C, Takatsuki F, Akiyama Y, Koike K, Ozawa K, Hirano T, Kishimoto T, Nakahata T, Asano S.In vitro expansion of murine pluripotent hemopoietic stem cell population in response to interleukin 3 and interleukin 6: application to bone marrow transplantation. Transplantation 1989; 48: 495–8.Google Scholar
  54. 54.
    Bot FJ, Van Eijk L, Broeders L, Aarden LA, Lowenber B. Interleukin-6 synergizes with M-CSF in the formation of macrophage colonies from purified human marrow progenitor cells. Blood 1989; 73: 435–7.Google Scholar
  55. 55.
    Caracciolo D, Clark SC, Rovera G. Human interleukin-6 supports granulocytic differentiation of hematopoietic progenitor cells and acts synergistically with GM-CSF. Blood 1989; 73: 666–70.Google Scholar
  56. 56.
    Suzuki C, Okano A, Takatsuki F, Miyasaka Y, Hirano T, Kishimoto T, Ejima D, Akiyama Y. Continuous perfusion with interleukin 6 (IL-6) enhances production of hematopoietic stem cells (CFU-S). Biochem Biophys Res Comm 1989; 159: 933–8.Google Scholar
  57. 57.
    Nagasawa T, Orita T, Matsushita J, Tsuchiya M, Neichi T, Imazeki I, Imai N, Ochi N, Kanma H, Abe T. Thrombopoietic activity of human interleukin-6. FEBS Lett 1990; 260: 176–9.Google Scholar
  58. 58.
    Suematsu S, Matsuda T, Aozasa K, Akira S, Nakano N, Ohno S, Miyazaki J, Yamamura K, Hirano T, Kishimoto T. IgG1 plasmacytosis in interleukin 6 transgenic mice. Proc Natl Acad Sci USA 1989; 86: 7547–51.Google Scholar
  59. 59.
    Nicola NA, Metcalf D, Matsumoto M, Johnson GR. Purification of a factor inducing differentiation in murine myelomonocytic leukemia cells. Identification as granulocyte colony-stimulating factor. J Biol Chem 1983; 258: 9017–23.Google Scholar
  60. 60.
    Sachs L. The molecular control of blood cell development. Science 1987; 238: 1374–9.Google Scholar
  61. 61.
    Shabo Y, Lotem J, Rubinstein M, Revel M, Clark SC, Wolf SF, Kamen R, Sachs L. The myeloid blood cell differentiation-inducing protein MGI-2A is interleukin 6. Blood 1988; 72: 2070–3.Google Scholar
  62. 62.
    Tomida M, Yamamoto-Yamaguchi Y, Hozumi M. Purification of a factor inducing differentiation of mouse myeloid leukemic M1 cells from conditioned medium of mouse fibroblast L929 cells. J Biol Chem 1984; 259: 10978–82.Google Scholar
  63. 63.
    Gearing D, Gough NM, King JA, Hilton DJ, Nicola NA, Simpson RJ, Nice EC, Kelso A, Metcalf D. Molecular cloning and expression of cDNA encoding a murine myeloid leukaemia inhibitory factor (LIF). EMBO J 1987; 6: 3995–4002.Google Scholar
  64. 64.
    Onozaki K, Akiyama Y, Okano A, Hirano T, Kishimoto T, Hashimoto T, Yoshizawa K, Taniyama T. Synergistic regulatory effects of interleukin 6 and interleukin 1 on the growth and differentiation of human and mouse leukemic cell lines. Cancer Res 1989; 49: 3602–7.Google Scholar
  65. 65.
    Chin C-P, Lee F. 1L-6 is a differentiation for M1 and WEHI-3B myeloid leukemic cells. J Immunol 1989; 142: 1909–15.Google Scholar
  66. 66.
    Hirano T, Taga T, Yasukawa K, Nakajima K, Nakano N, Takatsuki F, Shimizu M, Murashima A, Tsunasawa S, Sakiyama F, Kishimoto T. Human B cell differentiation factor defined by an anti-peptide antibody and its possible role in autoantibody production. Proc Natl Acad Sci USA 1987; 84: 228–31.Google Scholar
  67. 67.
    Yoshizaki K, Matsuda T, Nishimoto N, Kuritani T, Taeho L, Aozasa K, Nakahata T, Kawai H, Tagoh H, Komori T, Kishimoto S, Hirano T, Kishimoto T. Pathological Significance of interleukin 6 (IL-6/BSF-2) in Castleman's disease. Blood 1989; 74: 1360–7.Google Scholar
  68. 68.
    Breen EC, Rezai Ar, Nakajima K, Beall GN, Mitsuyasu RT, Hirano T, Kishimoto T, Martinez-Maza O. Infection with HIV is associated with elevated IL-6 levels and production. J Immunol 1990; 144: 480–4.Google Scholar
  69. 69.
    Deviere J, Content J, Denys C, Vandenbussche P, Schandene L, Wybran J, Dupont E. High interleukin-6 serum levels and increased production by leucocytes in alcoholic liver cirrhosis — correlation with IgA serum levels and lymphokines production. Clin Exp Immunol 1989; 77: 221–5.Google Scholar
  70. 70.
    Hirano T, and Kishimoto T. Interleukin 6 and plasma cell neoplasias progress in growth factor research 1989; 1: 133–42.Google Scholar
  71. 71.
    Van Damme J, Opdenakker G, Simpson RJ, Rubira MR, Cayphas S, Vink A, Billiau A, Snick JV. Identification of the human 26-kD protein, interferonβ2 (IFNβ2), as a B cell hybridoma/plasmacyoma growth factor induced by interleukin 1 and tumor necrosis factor. J Exp Med 1987; 165: 914–9.Google Scholar
  72. 72.
    Isobe T, Osserman EF. Pathologic conditions associated with plasma cell dyscrasias: a study of 806 cases. Annals New York Acad Sci 1971; 190: 507–17.Google Scholar
  73. 73.
    Isomaki HA, Hakulinen T, Joutsenlahti U. Excess risk of lymphomas, leukemia and myeloma in patients with rheumatoid arthritis. J Chron Dis 1978; 31: 691–6.Google Scholar
  74. 74.
    Wegelius O, Skrifvars B, Andersson L. Rheumatoid arthritis terminating in plasmacytoma. Acta Med Scand 1970; 187: 133–8.Google Scholar
  75. 75.
    Graham SL, Sellers AL. Atrial myxoma with multiple myeloma. Arch Intern Med 1979; 139: 116–7.Google Scholar
  76. 76.
    Keller AR, Hochholzer L, and Castleman B. Hyalin-vascular and plasma cell types of giant lymph node hyperplasia of the mediastinum and other locations. Cancer 1972; 29: 670–83.Google Scholar
  77. 77.
    Potter M, Boyce C. Induction of plasma cell neoplasms in strain Balb/c mice with mineral oil and mineral oil adjuvants. Nature 1962; 193: 1086–7.Google Scholar
  78. 78.
    Nordan RP, Potter M. A macrophage-derived factor required by plasmacytomas for survival and proliferationin vitro. Science 1986; 233: 566–9.Google Scholar
  79. 79.
    Namba Y, Hanaoka M. Immunocytology of cultured IgM-forming cells of mouse. I. Requirement of phagocytic cells factor and its role in antibody formation. J Immunol 1972; 109: 1193–200.Google Scholar
  80. 80.
    Ohno S, Babonits M, Wiener F, Spira J, Klein G, Potter M. Nonrandom chromosome changes involving the Ig gene-carrying chromosomes 12 and 6 in pristaine-induced mouse plasmacytomas. Cell 1979; 18: 1001–7.Google Scholar
  81. 81.
    Shimizu S, Hirano T, Yoshioka K, Sugai S, Matsuda T, Taga T, Kishimoto T, Konda S. Interleukin 6 (B cell stimulatory factor 2)-dependent growth of a Lennert's lymphoma-derived T cell line (KT-3). Blood 1988; 72: 1826–8.Google Scholar
  82. 82.
    Miki S, Iwano M, Miki Y, Yamamoto M, Tang B, Yokokawa K, Sonoda T, Hirano T, Kishimoto T. Interleukin-6 (IL-6) functions as anin vitro autocrine growth factor in renal cell carcinomas. FEBS Lett 1989; 250: 607–10.Google Scholar

Copyright information

© Kluwer Academic Publishers 1990

Authors and Affiliations

  • Tadashi Matsuda
    • 1
  • Toshio Hirano
    • 1
  1. 1.Division of Molecular Oncology, Biomedical Research CenterOsaka University Medical SchoolKita-ku, OsakaJapan

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