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 on 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. 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-oligomerization, 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, ENSFM00250000000777), which phosphorylate the receptor and thereby facilitate the recruitment of signal transducers and activators of transcription (STATs, ENSFM00500000269705, ENSFM00500000269817). The activated homo- or heterodimeric STATs function principally as transcription factors in the nucleus.

The IL-2, IL-3, IL-6, IL-12 and prolactin families of receptors are classified as type I cytokine receptors, while the interferon, IL-10 and IL-17 families of receptors and the immunoglobulin-like family of IL-1 like receptors are classified as type II cytokine receptors.

The IL-2 family of cytokines bind to heterodimeric receptors with ligand-selective α or β chains, and a common γ chain (γ_c) (IL2RG, ENSG00000147168, also known as CD132, CIDX, IMD4, severe combined immunodeficiency, SCIDX1).

IL13RA2 acts as a substitute for γ_c producing a non-signalling complex; a decoy receptor.

Endogenous agonists include IL-2 (ENSG00000109471, also known as T-cell growth factor, TCGF, aldesleukin), IL-4 (ENSG00000113520, also known as B-cell stimulatory factor 1, lymphocyte stimulatory factor 1, binetrakin, pitrakinra), IL-7 (ENSG00000104432), IL-9 (ENSG00000145839, also known as HP40, P40), IL-13 (ENSG00000169194), IL-15 (ENSG00000164136), IL-21 (ENSG00000138684, also known as ZA11) and thymic stromal lymphopoietin (TSLP, ENSG00000145777).

Ro264550 has been described as a selective IL-2 receptor antagonist, which binds to IL-2 [3].

The IL-3 family signal through a receptor complex comprising of a ligand-specific α subunit and a common β chain (CSF2RB, ENSG00000100368, also known as CD131, IL3RB or IL5RB), which is shared between all members of this cytokine family.

Endogenous agonists include IL-3 (ENSG00000164399, also known as multipotential colony-stimulating factor, hematopoietic growth factor, P-cell-stimulating factor, mast cell growth factor), IL-5 (ENSG00000113525, also known as EDF, TRF), GM-CSF (ENSG00000164400), and G-CSF (ENSG00000108342).

The IL-6 family signal through a ternary receptor complex consisting of the cognate receptor and a homodimer of the IL-6 signal transducer gp130 (IL6ST, ENSG00000134352, also known as CD130, oncostatin M receptor), 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. CRLF1 (cytokine receptor-like factor 1, ENSG00000006016, also known as CISS, CISS1, CLF, CLF-1, NR6) acts as an endogenous antagonist for the CNTF receptor.

Endogenous agonists include IL-6 (ENSG00000136244, also known as B-cell stimulatory factor 2, interferon β-2, hybridoma growth factor, CTL differentiation factor), IL-11 (ENSG00000095752, also known as adipogenesis inhibitory factor), ciliary neurotrophic factor (CNTF, ENSG00000242689), cardiotrophin-1 (CTF1, ENSG00000150281, also known as B-cell stimulatory factor 3, BSF3), cardiotrophin-like cytokine (CLCF1, ENSG00000175505), leptin (LEP, ENSG00000174697, also known as OB), leukemia inhibitory factor (LIF, ENSG00000128342, also known as cholinergic differentiation factor) and Oncostatin M (OSM, ENSG00000099985).

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 or homodimer of IL-12B/IL-12B subunits, while that for IL-23 receptors is a heterodimer of IL-12A/IL-23A.

Endogenous agonists include IL-12A (ENSG00000168811, also known as CLMF, IL-12A, NFSK, NKSF1, p35), IL-12B (ENSG00000113302, also known as natural killer cell stimulatory factor 2, cytotoxic lymphocyte maturation factor 2, p40) and IL-23A (ENSG00000110944).

The prolactin receptor family is made up of homodimeric receptor tyrosine kinases.

Endogenous agonists are large (~200 aa) polypeptides, and include erythropoietin (EPO, ENSG00000130427), granulocyte-macrophage colony stimulating factor (GM-CSF, ENSG00000164400, also known as colony-stimulating factor, CSF, sargramostim, molgramostin), growth hormone 1 (GH1, ENSG00000259384), growth hormone 2 (GH2, ENSG00000136487, also known as placenta-specific growth hormone), choriomammotropin (CSH1, ENSG00000136488, also known as lactogen), thrombopoietin (TPO, ENSG00000090534, also known as megakaryocyte colony-stimulating factor, myeloproliferative leukemia virus oncogene ligand, C-mpl ligand, megakaryocyte growth and development factor, MGDF), chorionic somatomammotropin hormone 2 (CSH2, ENSG00000213218), chorionic somatomammotropin hormone-like 1 (CSHL, ENSG00000204414, also known as lactogen-like) and granulocyte colony stimulating factor (CSF3, ENSG00000108342, also known as G-CSF, pluripoietin, filgrastim, lenograstim).

The interferon receptor family includes receptors for type I and type II interferons, that bind to heterodimeric receptors made up of IFNAR1/IFNAR2 or IFNGR1/IFNGR2, respectively.

Endogenous agonists in man include IFN-α1/13 (IFNA1, ENSG00000197919), IFN-β (IFNB1, ENSG00000171855), IFN-γ (IFNG, ENSG00000111537), IFN-κ (IFNK, ENSG00000147896) and IFN-ω (IFNW1, ENSG00000177047).

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, IL-28B and IL-29.

Endogenous agonists are IL-10 (ENSG00000136634), IL-19 (ENSG00000142224), IL-20 (ENSG00000162891), IL-22 (ENSG00000127318), IL-24 (ENSG00000162892), IL-28A (IL28A, ENSG00000183709, also known as IFN-λ2), IL-28B (IL28B, ENSG00000197110, also known as IFN-λ3), IL-29 (ENSG00000182393).

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, ENSG00000196083, also known as C3orf13, IL-1RAcP, IL1R3).

IL1R2, the type II IL-1 receptor (ENSG00000115590, also known as CD121b, IL1RB), is a decoy receptor, while the IL-1 receptor antagonist (IL1RN, ENSG00000136689, also known as ICIL-1RA, IL1F3, IL1RA, IRAP) prevents IL-1 binding to the receptor. Analogues of IL1RAP have been identified in the human genome: IL-1 receptor accessory protein-like 1 protein (IL1RAPL1, ENSG00000169306, also known as IL1R8, IL1RAPL, MRX10, MRX21, MRX34, OPHN4 or TIGIRR-2), X-linked IL-1 receptor accessory protein-like 2 (IL1RAPL2, ENSG00000189108, also known as IL-1R9, IL1R9, IL1RAPL-2 or TIGIRR-1) and IL-18 receptor accessory protein-like (IL18RAP, ENSG00000115607, also known asAcPL, CD218b).

Endogenous agonists are IL-1α (IL1A, ENSG00000115008, also known as IL-1 or IL-1F1), IL-1β (ENSG00000125538, also known as IL-1F2) and IL-18 (ENSG00000150782, also known as IFN-γ-inducing factor).

AF12198 has been described as a selective Type I IL-1 receptor antagonist [1].

The IL-17 receptor family appear to represent a distinct class of cytokine receptors with incompletely defined signalling.

Endogenous agonists include IL-17A (ENSG00000112115, also known as cytotoxic T-lymphocyte-associated serine esterase 8; CTLA8).

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