IL-6 signal transduction and its physiological roles: the signal orchestration model |
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Authors: | D Kamimura K Ishihara and T Hirano |
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Institution: | (1) Department of Molecular Oncology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan;(2) Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences , Osaka University, Osaka, Japan;(3) Laboratory for Cytokine Signaling, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan |
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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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