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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
Akdis M, Burgler S, Crameri R, Eiwegger T, Fujita H, Gomez E, Klunker S, Meyer N, O'Mahony L, Palomares O et al.. (2011) Interleukins, from 1 to 37, and interferon-γ: receptors, functions, and roles in diseases. J. Allergy Clin. Immunol., 127 (3): 701-21.e1-70. [PMID:21377040]
Brocker C, Thompson D, Matsumoto A, Nebert DW, Vasiliou V. (2010) Evolutionary divergence and functions of the human interleukin (IL) gene family. Hum. Genomics, 5 (1): 30-55. [PMID:21106488]
* Broughton SE, Dhagat U, Hercus TR, Nero TL, Grimbaldeston MA, Bonder CS, Lopez AF, Parker MW. (2012) The GM-CSF/IL-3/IL-5 cytokine receptor family: from ligand recognition to initiation of signaling. Immunol. Rev., 250 (1): 277-302. [PMID:23046136]
* Chang SH, Dong C. (2011) Signaling of interleukin-17 family cytokines in immunity and inflammation. Cell. Signal., 23 (7): 1069-75. [PMID:21130872]
* Donnelly RP, Dickensheets H, O'Brien TR. (2011) Interferon-lambda and therapy for chronic hepatitis C virus infection. Trends Immunol., 32 (9): 443-50. [PMID:21820962]
* George PM, Badiger R, Alazawi W, Foster GR, Mitchell JA. (2012) Pharmacology and therapeutic potential of interferons. Pharmacol. Ther., 135 (1): 44-53. [PMID:22484806]
* Gibbert K, Schlaak JF, Yang D, Dittmer U. (2013) IFN-α subtypes: distinct biological activities in anti-viral therapy. Br. J. Pharmacol., 168 (5): 1048-58. [PMID:23072338]
Liao W, Lin JX, Leonard WJ. (2011) IL-2 family cytokines: new insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation. Curr. Opin. Immunol., 23 (5): 598-604. [PMID:21889323]
Liongue C, Ward AC. (2007) Evolution of Class I cytokine receptors. BMC Evol. Biol., 7: 120. [PMID:17640376]
* Mackall CL, Fry TJ, Gress RE. (2011) Harnessing the biology of IL-7 for therapeutic application. Nat. Rev. Immunol., 11 (5): 330-42. [PMID:21508983]
Marcucci R, Romano M. (2008) Thrombopoietin and its splicing variants: structure and functions in thrombopoiesis and beyond. Biochim. Biophys. Acta, 1782 (7-8): 427-32. [PMID:18433726]
* Mihara M, Hashizume M, Yoshida H, Suzuki M, Shiina M. (2012) IL-6/IL-6 receptor system and its role in physiological and pathological conditions. Clin. Sci., 122 (4): 143-59. [PMID:22029668]
* Miller AM, Liew FY. (2011) The IL-33/ST2 pathway--A new therapeutic target in cardiovascular disease. Pharmacol. Ther., 131 (2): 179-86. [PMID:21356240]
* Miossec P, Kolls JK. (2012) Targeting IL-17 and TH17 cells in chronic inflammation. Nat Rev Drug Discov, 11 (10): 763-76. [PMID:23023676]
* Murugaiyan G, Saha B. (2013) IL-27 in tumor immunity and immunotherapy. Trends Mol Med, 19 (2): 108-16. [PMID:23306374]
* Palmer G, Gabay C. (2011) Interleukin-33 biology with potential insights into human diseases. Nat Rev Rheumatol, 7 (6): 321-9. [PMID:21519352]
* Pappu R, Ramirez-Carrozzi V, Sambandam A. (2011) The interleukin-17 cytokine family: critical players in host defence and inflammatory diseases. Immunology, 134 (1): 8-16. [PMID:21726218]
* Pappu R, Rutz S, Ouyang W. (2012) Regulation of epithelial immunity by IL-17 family cytokines. Trends Immunol., 33 (7): 343-9. [PMID:22476048]
* Parker D, Prince A. (2011) Type I interferon response to extracellular bacteria in the airway epithelium. Trends Immunol., 32 (12): 582-8. [PMID:21996313]
* Pestka S, Krause CD, Sarkar D, Walter MR, Shi Y, Fisher PB. (2004) Interleukin-10 and related cytokines and receptors. Annu. Rev. Immunol., 22: 929-79. [PMID:15032600]
* Rincon M. (2012) Interleukin-6: from an inflammatory marker to a target for inflammatory diseases. Trends Immunol., 33 (11): 571-7. [PMID:22883707]
* Rubino SJ, Geddes K, Girardin SE. (2012) Innate IL-17 and IL-22 responses to enteric bacterial pathogens. Trends Immunol., 33 (3): 112-8. [PMID:22342740]
* Sato N, Miyajima A. (1994) Multimeric cytokine receptors: common versus specific functions. Curr. Opin. Cell Biol., 6 (2): 174-9. [PMID:8024807]
* Schindler C, Levy DE, Decker T. (2007) JAK-STAT signaling: from interferons to cytokines. J. Biol. Chem., 282 (28): 20059-63. [PMID:17502367]
* Shevach EM. (2012) Application of IL-2 therapy to target T regulatory cell function. Trends Immunol., 33 (12): 626-32. [PMID:22951308]
* Steel JC, Waldmann TA, Morris JC. (2012) Interleukin-15 biology and its therapeutic implications in cancer. Trends Pharmacol. Sci., 33 (1): 35-41. [PMID:22032984]
* Tanaka T, Narazaki M, Kishimoto T. (2012) Therapeutic targeting of the interleukin-6 receptor. Annu. Rev. Pharmacol. Toxicol., 52: 199-219. [PMID:21910626]
* van der Lely AJ, Kopchick JJ. (2006) Growth hormone receptor antagonists. Neuroendocrinology, 83 (3-4): 264-8. [PMID:17047392]
* Wojno ED, Hunter CA. (2012) New directions in the basic and translational biology of interleukin-27. Trends Immunol., 33 (2): 91-7. [PMID:22177689]
* Zepp J, Wu L, Li X. (2011) IL-17 receptor signaling and T helper 17-mediated autoimmune demyelinating disease. Trends Immunol., 32 (5): 232-9. [PMID:21493143]
* Zhu S, Qian Y. (2012) IL-17/IL-17 receptor system in autoimmune disease: mechanisms and therapeutic potential. Clin. Sci., 122 (11): 487-511. [PMID:22324470]
1. Akeson AL, Woods CW, Hsieh LC, Bohnke RA, Ackermann BL, Chan KY, Robinson JL, Yanofsky SD, Jacobs JW, Barrett RW et al.. (1996) AF12198, a novel low molecular weight antagonist, selectively binds the human type I interleukin (IL)-1 receptor and blocks in vivo responses to IL-1. J. Biol. Chem., 271 (48): 30517-23. [PMID:8940020]
2. Dripps DJ, Verderber E, Ng RK, Thompson RC, Eisenberg SP. (1991) Interleukin-1 receptor antagonist binds to the type II interleukin-1 receptor on B cells and neutrophils. J. Biol. Chem., 266 (30): 20311-5. [PMID:1834644]
3. Fan Q, Leuther KK, Holmes CP, Fong KL, Zhang J, Velkovska S, Chen MJ, Mortensen RB, Leu K, Green JM et al.. (2006) Preclinical evaluation of Hematide, a novel erythropoiesis stimulating agent, for the treatment of anemia. Exp. Hematol., 34 (10): 1303-11. [PMID:16982323]
4. Morokata T, Ida K, Yamada T. (2002) Characterization of YM-90709 as a novel antagonist which inhibits the binding of interleukin-5 to interleukin-5 receptor. Int. Immunopharmacol., 2 (12): 1693-702. [PMID:12469943]
5. Tilley JW, Chen L, Fry DC, Emerson SD, Powers GD, Biondi D, Varnell T, Trilles R, Guthrie R, Mennona F, Kaplan G, LeMahieu RA, Carson M, Han RJ, Liu CM, Palermo R, Ju G. (1997) Identification of a small molecule inhibitor of the IL-2/IL-2R alpha receptor interaction which binds to IL-2. Journal of the American Chemical Society, 119 (32): 7589-7590.
6. Trainer PJ, Drake WM, Katznelson L, Freda PU, Herman-Bonert V, van der Lely AJ, Dimaraki EV, Stewart PM, Friend KE, Vance ML et al.. (2000) Treatment of acromegaly with the growth hormone-receptor antagonist pegvisomant. N. Engl. J. Med., 342 (16): 1171-7. [PMID:10770982]
7. Ward AC, Touw I, Yoshimura A. (2000) The Jak-Stat pathway in normal and perturbed hematopoiesis. Blood, 95 (1): 19-29. [PMID:10607680]