Phosphorylated STAT1, STAT3 form dimers Phosphorylated STATs are released Serine phosphorylation of STATs SOCS3 binds gp130 SHP2 is phosphorylated SHP2 binds gp130 phosphotyrosine-759 STAT1/3 dimers translocate to the nucleus SHP2 binds c-Cbl upon IL-6 stimulation JAKs associate with IL6RB (gp130) IL6:sIL6R binds to JAKs:IL6RB (gp130) Interleukin-6 binds to IL-6 receptor alpha subunit Assembly of a hexameric IL-6 receptor IL6:IL6RA binds JAKs:IL6RB (gp130) IL6:sIL6R binds sgp130 Interleukin-6 binds to soluble IL-6 receptor JAK activation Phosphorylation of gp130 STATs bind gp130 phosphotyrosines Tyrosine phosphorylation of STATs by IL6 receptor PathwayStep7199 PathwayStep7198 PathwayStep7193 PathwayStep7192 PathwayStep7197 PathwayStep7196 PathwayStep7195 PathwayStep7194 PathwayStep7210 PathwayStep7207 PathwayStep7206 PathwayStep7209 PathwayStep7208 PathwayStep7200 PathwayStep7201 PathwayStep7204 PathwayStep7205 PathwayStep7202 PathwayStep7203 Interleukin-6 signaling Authored: Ray, K, 2010-12-13 Edited: Jupe, S, 2010-12-10 Interleukin-6 (IL-6) is a pleiotropic cytokine with roles in processes including immune regulation, hematopoiesis, inflammation, oncogenesis, metabolic control and sleep. It is the founding member of a family of IL-6-related cytokines such as IL-11, IL-27 leukemia inhibitory factor (LIF), cilliary neurotrophic factor (CNTF) and oncostatin M. <br><br>The IL-6 receptor (IL6R) consists of an alpha subunit that specifically binds IL-6 and a beta subunit, IL6RB or gp130, which is the signaling component of all the receptors for cytokines related to IL-6. IL6R alpha exists in transmembrane and soluble forms. The transmembrane form is mainly expressed by hepatocytes, neutrophils, monocytes/macrophages, and some lymphocytes. Soluble forms of IL6R (sIL6R) are also expressed by these cells. Two major mechanisms for the production of sIL6R have been proposed. Alternative splicing generates a transcript lacking the transmembrane domain by using splicing donor and acceptor sites that flank the transmembrane domain coding region. This also introduces a frameshift leading to the incorporation of 10 additional amino acids at the C terminus of sIL6R.A second mechanism for the generation of sIL6R is the proteolytic cleavage or 'shedding' of membrane-bound IL-6R. Two proteases ADAM10 and ADAM17 are thought to contribute to this (Briso et al. 2008). sIL6R can bind IL6 and stimulate cells that express gp130 but not IL6R alpha, a process that is termed trans-signaling. This explains why many cells, including hematopoietic progenitor cells, neuronal cells, endothelial cells, smooth muscle cells, and embryonic stem cells, do not respond to IL6 alone, but show a remarkable response to IL6/sIL6R. It is clear that the trans-signaling pathway is responsible for the pro-inflammatory activities of IL-6 whereas the membrane bound receptor governs regenerative and anti-inflammatory IL-6 activities<br><br>IL6R signal transduction is mediated by two pathways:the JAK-STAT (Janus family tyrosine kinase-signal transducer and activator of transcription) pathway and the Ras-MAPK (mitogen-activated protein kinase) pathway. Negative regulators of IL-6 signaling include SOCS (suppressor of cytokine signals) and SHP2. Within the last few years different antibodies have been developed to inhibit IL-6 activity, and the first such antibodies have been introduced into the clinic for the treatment of inflammatory diseases (Kopf et al. 2010). Pubmed18490707 Pubmed20410258 Pubmed20811382 Reactome Database ID Release 431059683 Reactome, http://www.reactome.org ReactomeREACT_27307 Reviewed: Rose-John, S, 2011-02-11