1932

Abstract

▪ Abstract 

This essay summarizes my 40 years of research in immunology. As a young physician, I encountered a patient with Waldenström's macroglobulinemia, and this inspired me to study the structure of IgM. I began to ask how antibody responses are regulated. In the late 1960s, the essential role of T cells in antibody production had been reported. In search of molecules mediating T cell helper function, I discovered activities in the culture supernatant of T cells that induced proliferation and differentiation of B cells. This led to my life's work: studying one of those factors, interleukin-6 (IL-6). To my surprise, IL-6 turned out to play additional roles, including myeloma growth factor and hepatocyte-stimulating factor activities. More importantly, it was involved in a number of diseases, such as rheumatoid arthritis and Castleman's disease. I feel exceptionally fortunate that my work not only revealed the framework of cytokine signaling, including identification of the IL-6 receptor, gp130, NF-IL6, STAT3, and SOCS-1, but also led to the development of a new therapy for chronic inflammatory diseases.

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2005-04-23
2024-05-21
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Literature Cited

  1. Miller F, Metzger H. 1965. Characterization of a human macroglobulin. II. Distribution of the disulfide bonds. J. Biol. Chem. 240:4740–45 [Google Scholar]
  2. Lamm ME, Small PA Jr.. 1966. Polypeptide chain structure of rabbit immunoglobulins. II. γM-immunoglobulin. Biochemistry 5:267–76 [Google Scholar]
  3. Onoue K, Kishimoto T, Yamamura Y. 1968. Structure of human immunoglobulin M. II. Isolation of a high molecular weight Fc fragment of IgM composed of several Fc subunits J. Immunol. 100:238–44 [Google Scholar]
  4. Kishimoto T, Onoue K, Yamamura Y. 1968. Structure of human immunoglobulin M. 3. Pepsin fragmentation of IgM. J. Immunol. 100:1032–40 [Google Scholar]
  5. Svehag SE, Chesebro B, Bloth B. 1967. Ultrastructure of γM immunoglobulin and α macroglobulin: electron-microscopic study. Science 158:933–36 [Google Scholar]
  6. Ishizaka K, Ishizaka T, Terry WD. 1967. Antigenic structure of γE-globulin and reaginic antibody. J. Immunol. 99:849–58 [Google Scholar]
  7. Miller JF, Mitchell GF. 1968. Cell to cell interaction in the immune response. I. Hemolysin-forming cells in neonatally thymectomized mice reconstituted with thymus or thoracic duct lymphocytes J. Exp. Med. 128:801–20 [Google Scholar]
  8. Claman HN, Chaperon EA, Selner JC. 1968. Thymus-marrow immunocompetence. 3. The requirement for living thymus cells. Proc. Soc. Exp. Biol. Med. 127:462–66 [Google Scholar]
  9. Ishizaka K, Kishimoto T. 1972. Regulation of antibody response in vitro. II. Formation of rabbit reaginic antibody. J. Immunol. 109:65–73 [Google Scholar]
  10. Schimpl A, Wecker E. 1973. Studies on the source and action of the T-cell replacing factor (TRF). Adv. Exp. Med. Biol. 29:179–82 [Google Scholar]
  11. Kishimoto T, Ishizaka K. 1973. Regulation of antibody response in vitro. VII. Enhancing soluble factors for IgG and IgE antibody response J. Immunol. 111:1194–205 [Google Scholar]
  12. Kishimoto T, Ishizaka K. 1973. Regulation of antibody response in vitro. VI. Carrier-specific helper cells for IgG and IgE antibody response J. Immunol. 111:720–32 [Google Scholar]
  13. Kishimoto T, Ishizaka K. 1973. Regulation of antibody response in vitro. V. Effect of carrier-specific helper cells on generation of hapten-specific memory cells of different immunoglobulin classes J. Immunol. 111:1–9 [Google Scholar]
  14. Ishizaka T, Tomioka H, Ishizaka K. 1971. Degranulation of human basophil leukocytes by anti-γE antibody. J. Immunol. 106:705–10 [Google Scholar]
  15. Kishimoto T, Miyake T, Nishizawa Y, Watanabe T, Yamamura Y. 1975. Triggering mechanism of B lymphocytes. I. Effect of anti-immunoglobulin and enhancing soluble factor on differentiation and proliferation of B cells J. Immunol. 115:1179–84 [Google Scholar]
  16. Parker DC, Wadsworth DC, Schneider GB. 1980. Activation of murine B lymphocytes by anti-immunoglobulin is an inductive signal leading to immunoglobulin secretion. J. Exp. Med. 152:138–50 [Google Scholar]
  17. Howard M, Paul WE. 1983. Regulation of B-cell growth and differentiation by soluble factors. Annu. Rev. Immunol. 1:307–33 [Google Scholar]
  18. Nakanishi K, Howard M, Muraguchi A, Farrar J, Takatsu K. et al. 1983. Soluble factors involved in B cell differentiation: identification of two distinct T cell–replacing factors (TRF). J. Immunol. 130:2219–24 [Google Scholar]
  19. Hirano T, Kuritani T, Kishimoto T, Yamamura Y. 1977. In vitro immune response of human peripheral lymphocytes. I. The mechanism(s) involved in T cell helper functions in the pokeweed mitogen-induced differentiation and proliferation of B cells J. Immunol. 119:1235–41 [Google Scholar]
  20. Yoshizaki K, Nakagawa T, Kaieda T, Muraguchi A, Yamamura Y, Kishimoto T. 1982. Induction of proliferation and Ig production in human B leukemic cells by anti-immunoglobulins and T cell factors. J. Immunol. 128:1296–301 [Google Scholar]
  21. Ruscetti FW, Morgan DA, Gallo RC. 1977. Functional and morphologic characterization of human T cells continuously grown in vitro. J. Immunol. 119:131–38 [Google Scholar]
  22. Gillis S, Smith KA. 1977. Long term culture of tumour-specific cytotoxic T cells. Nature 268:154–56 [Google Scholar]
  23. Kishimoto T, Hirano T, Kuritani T, Yamamura Y, Ralph P, Good RA. 1978. Induction of IgG production in human B lymphoblastoid cell lines with normal human T cells. Nature 271:756–58 [Google Scholar]
  24. Howard M, Farrar J, Hilfiker M, Johnson B, Takatsu K. et al. 1982. Identification of a T cell–derived B cell growth factor distinct from interleukin 2. J. Exp. Med. 155:914–23 [Google Scholar]
  25. Takatsu K, Tominaga A, Hamaoka T. 1980. Antigen-induced T cell–replacing factor (TRF). I. Functional characterization of a TRF-producing helper T cell subset and genetic studies on TRF production J. Immunol. 124:2414–22 [Google Scholar]
  26. Swain SL, Dutton RW. 1982. Production of a B cell growth-promoting activity, (DL)BCGF, from a cloned T cell line and its assay on the BCL1 B cell tumor. J. Exp. Med. 156:1821–34 [Google Scholar]
  27. Kishimoto T. 1985. Factors affecting B-cell growth and differentiation. Annu. Rev. Immunol. 3:133–57 [Google Scholar]
  28. Taniguchi T, Matsui H, Fujita T, Takaoka C, Kashima N. et al. 1983. Structure and expression of a cloned cDNA for human interleukin-2. Nature 302:305–10 [Google Scholar]
  29. Noma Y, Sideras P, Naito T, Bergstedt-Lindquist S, Azuma C. et al. 1986. Cloning of cDNA encoding the murine IgG1 induction factor by a novel strategy using SP6 promoter. Nature 319:640–46 [Google Scholar]
  30. Hirano T, Yasukawa K, Harada H, Taga T, Watanabe Y. et al. 1986. Complementary DNA for a novel human interleukin (BSF-2) that induces B lymphocytes to produce immunoglobulin. Nature 324:73–76 [Google Scholar]
  31. Kinashi T, Harada N, Severinson E, Tanabe T, Sideras P. et al. 1986. Cloning of complementary DNA encoding T-cell replacing factor and identity with B-cell growth factor II. Nature 324:70–73 [Google Scholar]
  32. Hirano T, Taga T, Nakano N, Yasukawa K, Kashiwamura S. et al. 1985. Purification to homogeneity and characterization of human B-cell differentiation factor (BCDF or BSFp-2). Proc. Natl. Acad. Sci. USA 82:5490–94 [Google Scholar]
  33. Jourdan M, Bataille R, Seguin J, Zhang XG, Chaptal PA, Klein B. 1990. Constitutive production of interleukin-6 and immunologic features in cardiac myxomas. Arthritis Rheum. 33:398–402 [Google Scholar]
  34. Hirano T, Matsuda T, Hosoi K, Okano A, Matsui H, Kishimoto T. 1988. Absence of antiviral activity in recombinant B cell stimulatory factor 2 (BSF-2). Immunol. Lett. 17:41–45 [Google Scholar]
  35. Potter M, Boyce CR. 1962. Induction of plasma-cell neoplasms in strain BALB/c mice with mineral oil and mineral oil adjuvants. Nature 193:1086–87 [Google Scholar]
  36. Nordan RP, Pumphrey JG, Rudikoff S. 1987. Purification and NH2-terminal sequence of a plasmacytoma growth factor derived from the murine macrophage cell line P388D1. J. Immunol. 139:813–17 [Google Scholar]
  37. Suematsu S, Matsusaka T, Matsuda T, Ohno S, Miyazaki J. et al. 1992. Generation of plasmacytomas with the chromosomal translocation t(12;15) in interleukin 6 transgenic mice. Proc. Natl. Acad. Sci. USA 89:232–35 [Google Scholar]
  38. Kawano M, Hirano T, Matsuda T, Taga T, Horii Y. et al. 1988. Autocrine generation and requirement of BSF-2/IL-6 for human multiple myelomas. Nature 332:83–85 [Google Scholar]
  39. Gauldie J, Richards C, Harnish D, Lansdorp P, Baumann H. 1987. Interferon β2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells. Proc. Natl. Acad. Sci. USA 84:7251–55 [Google Scholar]
  40. Andus T, Geiger T, Hirano T, Northoff H, Ganter U. et al. 1987. Recombinant human B cell stimulatory factor 2 (BSF-2/IFN-β2) regulates β-fibrinogen and albumin mRNA levels in Fao-9 cells. FEBS Lett. 221:18–22 [Google Scholar]
  41. Kopf M, Baumann H, Freer G, Freudenberg M, Lamers M. et al. 1994. Impaired immune and acute-phase responses in interleukin-6-deficient mice. Nature 368:339–42 [Google Scholar]
  42. Seed B, Aruffo A. 1987. Molecular cloning of the CD2 antigen, the T-cell erythrocyte receptor, by a rapid immunoselection procedure. Proc. Natl. Acad. Sci. USA 84:3365–69 [Google Scholar]
  43. Yamasaki K, Taga T, Hirata Y, Yawata H, Kawanishi Y. et al. 1988. Cloning and expression of the human interleukin-6 (BSF-2/IFN β2) receptor. Science 241:825–28 [Google Scholar]
  44. Taga T, Hibi M, Hirata Y, Yamasaki K, Yasukawa K. et al. 1989. Interleukin-6 triggers the association of its receptor with a possible signal transducer, gp130. Cell 58:573–81 [Google Scholar]
  45. Hibi M, Murakami M, Saito M, Hirano T, Taga T, Kishimoto T. 1990. Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell 63:1149–57 [Google Scholar]
  46. Ip NY, Nye SH, Boulton TG, Davis S, Taga T. et al. 1992. CNTF and LIF act on neuronal cells via shared signaling pathways that involve the IL-6 signal transducing receptor component gp130. Cell 69:1121–32 [Google Scholar]
  47. Gearing DP, Comeau MR, Friend DJ, Gimpel SD, Thut CJ. et al. 1992. The IL-6 signal transducer, gp130: an oncostatin M receptor and affinity converter for the LIF receptor. Science 255:1434–37 [Google Scholar]
  48. Liu J, Modrell B, Aruffo A, Marken JS, Taga T. et al. 1992. Interleukin-6 signal transducer gp130 mediates oncostatin M signaling. J. Biol. Chem. 267:16763–66 [Google Scholar]
  49. Yin T, Taga T, Tsang ML, Yasukawa K, Kishimoto T, Yang YC. 1993. Involvement of IL-6 signal transducer gp130 in IL-11-mediated signal transduction. J. Immunol. 151:2555–61 [Google Scholar]
  50. Pennica D, Shaw KJ, Swanson TA, Moore MW, Shelton DL. et al. 1995. Cardiotrophin-1. Biological activities and binding to the leukemia inhibitory factor receptor/gp130 signaling complex J. Biol. Chem. 270:10915–22 [Google Scholar]
  51. Shabo Y, Lotem J, Rubinstein M, Revel M, Clark SC. et al. 1988. The myeloid blood cell differentiation-inducing protein MGI-2A is interleukin-6. Blood 72:2070–73 [Google Scholar]
  52. Hilton DJ, Nicola NA, Gough NM, Metcalf D. 1988. Resolution and purification of three distinct factors produced by Krebs ascites cells which have differentiation-inducing activity on murine myeloid leukemic cell lines. J. Biol. Chem. 263:9238–43 [Google Scholar]
  53. Akira S, Isshiki H, Sugita T, Tanabe O, Kinoshita S. et al. 1990. A nuclear factor for IL-6 expression (NF-IL6) is a member of a C/EBP family. EMBO J. 9:1897–906 [Google Scholar]
  54. Nakajima T, Kinoshita S, Sasagawa T, Sasaki K, Naruto M. et al. 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 90:2207–11 [Google Scholar]
  55. Murakami M, Narazaki M, Hibi M, Yawata H, Yasukawa K. et al. 1991. Critical cytoplasmic region of the interleukin 6 signal transducer gp130 is conserved in the cytokine receptor family. Proc. Natl. Acad. Sci. USA 88:11349–53 [Google Scholar]
  56. Murakami M, Hibi M, Nakagawa N, Nakagawa T, Yasukawa K. et al. 1993. IL-6-induced homodimerization of gp130 and associated activation of a tyrosine kinase. Science 260:1808–10 [Google Scholar]
  57. Silvennoinen O, Witthuhn BA, Quelle FW, Cleveland JL, Yi T, Ihle JN. 1993. Structure of the murine Jak2 protein-tyrosine kinase and its role in interleukin 3 signal transduction. Proc. Natl. Acad. Sci. USA 90:8429–33 [Google Scholar]
  58. Watling D, Guschin D, Muller M, Silvennoinen O, Witthuhn BA. et al. 1993. Complementation by the protein tyrosine kinase JAK2 of a mutant cell line defective in the interferon-γ signal transduction pathway. Nature 366:166–70 [Google Scholar]
  59. Silvennoinen O, Ihle JN, Schlessinger J, Levy DE. 1993. Interferon-induced nuclear signalling by Jak protein tyrosine kinases. Nature 366:583–85 [Google Scholar]
  60. Wegenka UM, Buschmann J, Lutticken C, Heinrich PC, Horn F. 1993. Acute-phase response factor, a nuclear factor binding to acute-phase response elements, is rapidly activated by interleukin-6 at the posttranslational level. Mol. Cell Biol. 13:276–88 [Google Scholar]
  61. Akira S, Nishio Y, Inoue M, Wang XJ, Wei S. et al. 1994. Molecular cloning of APRF, a novel IFN-stimulated gene factor 3 p91-related transcription factor involved in the gp130-mediated signaling pathway. Cell 77:63–71 [Google Scholar]
  62. 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 [Google Scholar]
  63. Naka T, Narazaki M, Hirata M, Matsumoto T, Minamoto S. et al. 1997. Structure and function of a new STAT-induced STAT inhibitor. Nature 387:924–29 [Google Scholar]
  64. Starr R, Willson TA, Viney EM, Murray LJ, Rayner JR. et al. 1997. A family of cytokine-inducible inhibitors of signalling. Nature 387:917–21 [Google Scholar]
  65. Endo TA, Masuhara M, Yokouchi M, Suzuki R, Sakamoto H. et al. 1997. A new protein containing an SH2 domain that inhibits JAK kinases. Nature 387:921–24 [Google Scholar]
  66. Kikutani H, Suemura M, Owaki H, Nakamura H, Sato R. et al. 1986. Fcϵ receptor, a specific differentiation marker transiently expressed on mature B cells before isotype switching. J. Exp. Med. 164:1455–69 [Google Scholar]
  67. Kikutani H, Inui S, Sato R, Barsumian EL, Owaki H. et al. 1986. Molecular structure of human lymphocyte receptor for immunoglobulin E. Cell 47:657–65 [Google Scholar]
  68. Yokota A, Kikutani H, Tanaka T, Sato R, Barsumian EL. et al. 1988. Two species of human Fcϵ receptor II (Fcϵ RII/CD23): tissue-specific and IL-4-specific regulation of gene expression. Cell 55:611–18 [Google Scholar]
  69. Nagasawa T, Kikutani H, Kishimoto T. 1994. Molecular cloning and structure of a pre-B-cell growth-stimulating factor. Proc. Natl. Acad. Sci. USA 91:2305–9 [Google Scholar]
  70. Nagasawa T, Hirota S, Tachibana K, Takakura N, Nishikawa S. et al. 1996. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 382:635–38 [Google Scholar]
  71. Nagasawa T, Nakajima T, Tachibana K, Iizasa H, Bleul CC. et al. 1996. Molecular cloning and characterization of a murine pre-B-cell growth-stimulating factor/stromal cell-derived factor 1 receptor, a murine homolog of the human immunodeficiency virus 1 entry coreceptor fusin. Proc. Natl. Acad. Sci. USA 93:1472629 [Google Scholar]
  72. Tachibana K, Hirota S, Iizasa H, Yoshida H, Kawabata K. et al. 1998. The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature 393:591–94 [Google Scholar]
  73. Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K. et al. 1997. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89:755–64 [Google Scholar]
  74. Hirano T, Matsuda T, Turner M, Miyasaka N, Buchan G. et al. 1988. Excessive production of interleukin 6/B cell stimulatory factor-2 in rheumatoid arthritis. Eur. J. Immunol. 18:1797–801 [Google Scholar]
  75. Yoshizaki K, Matsuda T, Nishimoto N, Kuritani T, Taeho L. et al. 1989. Pathogenic significance of interleukin-6 (IL-6/BSF-2) in Castleman's disease. Blood 74:136067 [Google Scholar]
  76. Soulier J, Grollet L, Oksenhendler E, Cacoub P, Cazals-Hatem D. et al. 1995. Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease. Blood 86:1276–80 [Google Scholar]
  77. Chatterjee M, Osborne J, Bestetti G, Chang Y, Moore PS. 2002. Viral IL-6-induced cell proliferation and immune evasion of interferon activity. Science 298:1432–35 [Google Scholar]
  78. Nishimoto N, Sasai M, Shima Y, Nakagawa M, Matsumoto T. et al. 2000. Improvement in Castleman's disease by humanized anti-interleukin-6 receptor antibody therapy. Blood 95:56–61 [Google Scholar]
  79. Ohshima S, Saeki Y, Mima T, Sasai M, Nishioka K. et al. 1998. Interleukin 6 plays a key role in the development of antigen-induced arthritis. Proc. Natl. Acad. Sci. USA 95:8222–26 [Google Scholar]
  80. Hata T, Sakaguchi N, Yoshitomi H, Iwakura Y, Sekikawa K. et al. 2004. Distinct contribution of IL-6, TNF-α, IL-1, and IL-10 to T cell–mediated spontaneous autoimmune arthritis in mice. J. Clin. Invest. 114:582–88 [Google Scholar]
  81. Nishimoto N, Yoshizaki K, Miyasaka N, Yamamoto K, Kawai S. et al. 2004. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum. 50:1761–69 [Google Scholar]
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