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November 2, 2004Annual Review of Immunology1,029 citations

INTERLEUKIN-6: From Basic Science to Medicine—40 Years in Immunology

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TKTadamitsu Kishimoto

Key Points

  • To review forty years of immunological research detailing the discovery of interleukin-6, the elucidation of its signaling cascade, and its translation into therapies for inflammatory diseases.
  • Historical narrative synthesis summarizing four decades of experimental immunology on antibody response regulation and cytokine biology.
  • Isolation and characterization of T-cell-derived B-cell differentiation factors and subsequent molecular identification of receptor complexes and intracellular signaling pathways.
  • Identified interleukin-6 (IL-6) as a pleiotropic cytokine functioning in B-cell differentiation, myeloma cell proliferation, and hepatocyte stimulation.
  • Characterized the molecular signaling architecture of IL-6, including the IL-6 receptor, gp130 signal transducer, NF-IL6 transcription factor, STAT3, and the negative regulator SOCS-1.
  • Established the pathological role of IL-6 overproduction in autoimmune and inflammatory disorders, including rheumatoid arthritis and Castleman's disease, enabling the development of therapeutic IL-6 inhibitors.

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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Tadamitsu Kishimoto (2004) studied this question.

synapsesocial.com/papers/69de9693499d77a496b0be87https://doi.org/10.1146/annurev.immunol.23.021704.115806
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