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Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Cytokines are not a clearly defined group of agents, other than having an impact on immune signalling pathways, although many cytokines have effects on other systems, such as in development. A feature of some cytokines, which allows them to be distinguished from hormones, is that they may be produced by “non-secretory” cells, for example, endothelial cells. Within the cytokine receptor family, some subfamilies may be identified, which are described elsewhere in the Guide to PHARMACOLOGY, receptors for the TNF family, the TGF-β family and the chemokines. Within this group of records are described Type I cytokine receptors, typified by interleukin receptors, and Type II cytokine receptors, exemplified by interferon receptors. These receptors possess a conserved extracellular region, known as the cytokine receptor homology domain (CHD), along with a range of other structural modules, including extracellular immunoglobulin (Ig)-like and fibronectin type III (FBNIII)-like domains, a transmembrane domain, and intracellular homology domains. An unusual feature of this group of agents is the existence of soluble and decoy receptors. These bind cytokines without allowing signalling to occur. A further attribute is the production of endogenous antagonist molecules, which bind to the receptors selectively and prevent signalling. A commonality of these families of receptors is the ligand-induced homo- or hetero-oligomerisation, which results in the recruitment of intracellular protein partners to evoke cellular responses, particularly in inflammatory or haematopoietic signalling. Although not an exclusive signalling pathway, a common feature of the majority of cytokine receptors is activation of the JAK/STAT pathway. This cascade is based around the protein tyrosine kinase activity of the Janus kinases (JAK), which phosphorylate the receptor and thereby facilitate the recruitment of signal transducers and activators of transcription (STATs). The activated homo- or heterodimeric STATs function principally as transcription factors in the nucleus.
Type I cytokine receptors are characterized by two pairs of conserved cysteines linked via disulfide bonds and a C-terminal WSXWS motif within their CHD. Type I receptors are commonly classified into five groups, based on sequence and structual homology of the receptor and its cytokine ligand, which is potentially more reflective of evolutionary relationships than an earlier scheme based on the use of common signal transducing chains within a receptor complex.
Type II cytokine receptors also have two pairs of conserved cysteines but with a different arrangement to Type I and also lack the WSXWS motif.
The IL-2 receptor family consists of one or more ligand-selective subunits, and a common γ chain (γc): IL2RG, P31785), though IL-4 and IL-7 receptors can form complexes with other receptor chains. Receptors of this family associate with Jak1 and Jak3, primarily activating Stat5, although certain family members can also activate Stat1, Stat3, or Stat6. Ro264550 has been described as a selective IL-2 receptor antagonist, which binds to IL-2 .
The IL-6 receptor family signal through a ternary receptor complex consisting of the cognate receptor and either the IL-6 signal transducer gp130 (IL6ST, P40189) or the oncostatin M-specific receptor, β subunit (OSMR, Q99650), which then activates the JAK/STAT, Ras/Raf/MAPK and PI 3-kinase/PKB signalling modules. Unusually amongst the cytokine receptors, the CNTF receptor is a glycerophosphatidylinositol-linked protein.
IL-12 receptors are a subfamily of the IL-6 receptor family. IL12RB1 is shared between receptors for IL-12 and IL-23; the functional agonist at IL-12 receptors is a heterodimer of IL-12A/IL-12B, while that for IL-23 receptors is a heterodimer of IL-12B/IL-23A.
Prolactin family receptors form homodimers in the presence of their respective ligands, associate exclusively with Jak2 and signal via Stat5.
The interferon receptor family includes receptors for type I (α, β κ and ω) and type II (γ) interferons. There are at least 13 different genesencoding IFN-&ALPHA; subunits in a cluster on human chromosome 9p22: α1 (IFNA1, P01562), α2 (IFNA2, P01563), α4 (IFNA4, P05014), α5 (IFNA5, P01569), α6 (IFNA6, P05013), α7 (IFNA7, P01567), α8 (IFNA8, P32881), α10 (IFNA10, P01566), α13 (IFNA13, P01562), α14 (IFNA14, P01570), α16 (IFNA16, P05015), α17 (IFNA17, P01571) and α21 (IFNA21, P01568).
The IL-10 family of receptors are heterodimeric combinations of family members: IL10RA/IL10RB responds to IL-10; IL20RA/IL20RB responds to IL-19, IL-20 and IL-24; IL22RA1/IL20RB responds to IL-20 and IL-24; IL22RA1/IL10RB responds to IL-22; IL28RA/IL10RB responds to IL-28A, IL28B and IL-29.
The immunoglobulin-like family of IL-1 receptors are heterodimeric receptors made up of a cognate receptor subunit and an IL-1 receptor accessory protein, IL1RAP (Q9NPH3, also known as C3orf13, IL-1RAcP, IL1R3). They are characterised by extracellular immunoglobulin-like domains and an intracellular Toll/Interleukin-1R (TIR) domain.
The IL17 cytokine family consists of six ligands (IL-17A-F), which signal through five receptors (IL-17RA-E).
* Key recommended reading is highlighted with an asterisk
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