IL-6 signal transduction and its physiological roles: the signal orchestration model
Identifieur interne : 000887 ( Main/Exploration ); précédent : 000886; suivant : 000888IL-6 signal transduction and its physiological roles: the signal orchestration model
Auteurs : D. Kamimura [Japon] ; K. Ishihara [Japon] ; T. Hirano [Japon]Source :
- Reviews of Physiology, Biochemistry and Pharmacology [ 0303-4240 ] ; 2004.
Abstract
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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DOI: 10.1007/s10254-003-0012-2
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Kamimura</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Molecular Oncology, Graduate School of Medicine, Osaka University, Suita, Osaka</wicri:regionArea><wicri:noRegion>Osaka</wicri:noRegion></affiliation></author><author><name sortKey="Ishihara, K" sort="Ishihara, K" uniqKey="Ishihara K" first="K." last="Ishihara">K. Ishihara</name><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Department of Molecular Oncology, Graduate School of Medicine, Osaka University, Suita, Osaka</wicri:regionArea><wicri:noRegion>Osaka</wicri:noRegion></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Japon</country><wicri:regionArea>Laboratory of Developmental Immunology, Graduate School of Frontier Biosciences, Osaka University, Osaka</wicri:regionArea><wicri:noRegion>Osaka</wicri:noRegion></affiliation></author><author><name sortKey="Hirano, T" sort="Hirano, T" uniqKey="Hirano T" first="T." last="Hirano">T. 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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.</div></front></TEI><affiliations><list><country><li>Japon</li></country></list><tree><country name="Japon"><noRegion><name sortKey="Kamimura, D" sort="Kamimura, D" uniqKey="Kamimura D" first="D." last="Kamimura">D. Kamimura</name></noRegion><name sortKey="Hirano, T" sort="Hirano, T" uniqKey="Hirano T" first="T." last="Hirano">T. Hirano</name><name sortKey="Hirano, T" sort="Hirano, T" uniqKey="Hirano T" first="T." last="Hirano">T. Hirano</name><name sortKey="Hirano, T" sort="Hirano, T" uniqKey="Hirano T" first="T." last="Hirano">T. Hirano</name><name sortKey="Hirano, T" sort="Hirano, T" uniqKey="Hirano T" first="T." last="Hirano">T. Hirano</name><name sortKey="Ishihara, K" sort="Ishihara, K" uniqKey="Ishihara K" first="K." last="Ishihara">K. Ishihara</name><name sortKey="Ishihara, K" sort="Ishihara, K" uniqKey="Ishihara K" first="K." last="Ishihara">K. Ishihara</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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