IL-6/IL-6 receptor system and its role in physiological and pathological conditions.
IL (interleukin)-6, which was originally identified as a B-cell differentiation factor, is a multifunctional cytokine that regulates the immune response, haemopoiesis, the acute phase response and inflammation. IL-6 is produced by various types of cell and influences various cell types, and has multiple biological activities through its unique receptor system. IL-6 exerts its biological activities through two molecules: IL-6R (IL-6 receptor) and gp130. When IL-6 binds to mIL-6R (membrane-bound form of IL-6R), homodimerization of gp130 is induced and a high-affinity functional receptor complex of IL-6, IL-6R and gp130 is formed. Interestingly, sIL-6R (soluble form of IL-6R) also binds with IL-6, and the IL-6-sIL-6R complex can then form a complex with gp130. The homodimerization of receptor complex activates JAKs (Janus kinases) that then phosphorylate tyrosine residues in the cytoplasmic domain of gp130. The gp130-mediated JAK activation by IL-6 triggers two main signalling pathways: the gp130 Tyr759-derived SHP-2 (Src homology 2 domain-containing protein tyrosine phosphatase-2)/ERK (extracellular-signal-regulated kinase) MAPK (mitogen-activated protein kinase) pathway and the gp130 YXXQ-mediated JAK/STAT (signal transducer and activator of transcription) pathway. Increased IL-6 levels are observed in several human inflammatory diseases, such as rheumatoid arthritis, Castleman's disease and systemic juvenile idiopathic arthritis. IL-6 is also critically involved in experimentally induced autoimmune diseases. All clinical findings and animal models suggest that IL-6 plays a number of critical roles in the pathogenesis of autoimmune diseases. In the present review, we first summarize the IL-6/IL-6R system and IL-6 signal transduction, and then go on to discuss the physiological and pathological roles of IL-6.
Fuji-Gotemba Research Laboratories, Product Research Department, Chugai Pharmaceutical Co. Ltd., Gotemba, Japan. miharamsh@chugai-pharm.co.jp
Masahiko
M
Mihara
Misato
M
Hashizume
Hiroto
H
Yoshida
Miho
M
Suzuki
Masashi
M
Shiina
D000818:Animals; D004194:Disease / Q000209:etiology; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D019947:Receptors, Interleukin-6 / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D000093242:Interleukin-6 Inhibitors
D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D000093242:Interleukin-6 Inhibitors