n many cell types while its receptor Il6r displays a rather restricted expression pattern; the transducer is ubiquitously expressed in most/all cell types. Il6 binds the membrane bound receptor Il6r and the binary complex then binds the family shared signal transducer. A soluble form of the receptor exists, resulting primarily from processing by members of the ADAM family of metalloproteases or to a lower extent, from alternative splicing. It binds Il6 with comparable affinity, associates with gp130 and activates target cells that do not express Il6r. Signaling via the membrane-bound Il6r or via the soluble Il6 are referred to as the classic and trans-signaling, respectively. Trans-signaling allows cells that do not express the receptor to mediate the effects of Il6. It could also un-necessarily augment Il6 effects and underlie pathological conditions. A soluble form of gp130 exists which binds the Il6/soluble-Il6r complex acting as an inhibitor of trans-signaling. The crystal structure of a ternary complex reveals a hexameric structure with two molecules of Il6, Il6r and Il6st/gp130. However, whether the hexamer or a postulated tetramer is the biological significant complex, remains to be established. Via gp130, Il6 triggers Jak-Stat and the Raf/Mek/Erk MAPK intracellular pathways, whose independent signaling underlie the many Il6 mediated effects. Once complexed with Il6 and Il6r, Gp130 activates Jak protein kinases leading to the phosphorylation of tyrosine residues on gp130 cytoplasmic domain. Phosphorylated YxxQ motifs recruit Stat(s) (Stat1 and Stat3) which are then phosphorylated by Jak(s) and translocate to the nucleus to activate the transcription of target genes. Phosphorylation of gp130 tyrosine759 (human) leads to recruitment of Ptpn11 (Shp2), which is then phosphorylated by Jak(s). Activated Ptpn11 recruits Grb2 which is constitutively associated with Sos proteins, the GDP/GTP exchangers of Ras. GTP-bound Ras prompts the activation of the first MAP3K tier of the Raf/Mek/Erk cascade. Il6 signaling plays an essential role in regulating the balance between regulatory T cells (Treg) and effector Th17 cells which is crucial for the maintenance of immune homeostasis. Il6, in concert with Tgf-beta signaling, promotes differentiation of Th17 cells while inhibiting the differentiation of Tgf-beta mediated Treg cells. Overexpression of Il-6 and excessive signaling have been associated with a wide variety of conditions. Pathologic roles of Il6 include inflammation and autoimmunity, rheumatoid arthritis, multiple sclerosis and neurodegeneration. Tocilizumab - trade name Acterma, is a humanized anti-Il6 receptor antibody; it binds both the membrane-bound and the soluble receptors inhibiting their interaction with Il6. To see the ontology report for annotations, GViewer and download, click here [click to see associated GO term - GO:0070102 and entry at Reactome - REACT_27307.1.]...(less)