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Reviews of Physiology, Biochemistry and Pharmacology pp 1–38Cite as

IL-6 signal transduction and its physiological roles: the signal orchestration model

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Part of the book series: Reviews of Physiology, Biochemistry and Pharmacology ((REVIEWS,volume 149))

Abstract

Interleukin (IL)-6 is a pleiotropic cytokine that not only affects the immune system, but also acts in other biological systems and many physiological events in various organs. In a target cell, IL-6 can simultaneously generate functionally distinct or sometimes contradictory signals through its receptor complex, IL-6Rα and gp130. One good illustration is derived from the in vitro observations that IL-6 promotes the growth arrest and differentiation of M1 cells through gp130-mediated STAT3 activation, whereas the Y759/SHP-2-mediated cascade by gp130 stimulation has growth-enhancing effects. The final physiological output can be thought of as a consequence of the orchestration of the diverse signaling pathways generated by a given ligand. This concept, the signal orchestration model, may explain how IL-6 can elicit proinflammatory or anti-inflammatory effects, depending on the in vivo environmental circumstances. Elucidation of the molecular mechanisms underlying this issue is a challenging subject for future research. Intriguingly, recent in vivo studies indicated that the SHP-2-binding site- and YXXQ-mediated pathways through gp130 are not mutually exclusive but affect each other: a mutation at the SHP-2-binding site prolongs STAT3 activation, and a loss of STAT activation by gp130 truncation leads to sustained SHP-2/ERK MAPK phosphorylation. Although IL-6/gp130 signaling is a promising target for drug discovery for many human diseases, the interdependence of each signaling pathway may be an obstacle to the development of a nonpeptide orally active small molecule to inhibit one of these IL-6 signaling cascades, because it would disturb the signal orchestration. In mice, a consequence of the imbalanced signals causes unexpected results such as gastrointestinal disorders, autoimmune diseases, and/or chronic inflammatory proliferative diseases. However, lessons learned from IL-6 KO mice indicate that IL-6 is not essential for vital biological processes, but a significant impact on disease progression in many experimental models for human disorders. Thus, IL-6/gp130 signaling will become a more attractive therapeutic target for human inflammatory diseases when a better understanding of IL-6 signaling, including the identification of the conductor for gp130 signal transduction, is achieved.

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Authors and Affiliations

  1. Department of Molecular Oncology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan

    D. Kamimura, K. Ishihara & T. Hirano

  2. Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan

    K. Ishihara & T. Hirano

  3. Laboratory for Cytokine Signaling, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan

    T. Hirano

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  1. D. Kamimura
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  2. K. Ishihara
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  3. T. Hirano
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Correspondence to T. Hirano .

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Kamimura, D., Ishihara, K., Hirano, T. (2003). IL-6 signal transduction and its physiological roles: the signal orchestration model. In: Reviews of Physiology, Biochemistry and Pharmacology. Reviews of Physiology, Biochemistry and Pharmacology, vol 149. Springer, Berlin, Heidelberg. https://doi.org/10.1007/s10254-003-0012-2

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  • DOI: https://doi.org/10.1007/s10254-003-0012-2

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