IL-6 signal transduction and its physiological roles: the signal orchestration model.
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-6Ralpha 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.
Kamimura
D
D
Department of Molecular Oncology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
Ishihara
K
K
Hirano
T
T
D000210:Acute-Phase Reaction / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology; D001327:Autoimmune Diseases / Q000276:immunology; D001842:Bone and Bones / Q000276:immunology / Q000378:metabolism; D050822:Cytokine Receptor gp130; D006410:Hematopoiesis / Q000276:immunology; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D018448:Models, Immunological; D008969:Molecular Sequence Data; D009154:Mutation; D009369:Neoplasms / Q000276:immunology; D009490:Neurosecretory Systems / Q000276:immunology; D010641:Phenotype; D019947:Receptors, Interleukin-6 / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000276:immunology*
D015703:Antigens, CD; C494199:IL6ST protein, human; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D019947:Receptors, Interleukin-6; D050822:Cytokine Receptor gp130