Interleukins are a group of cytokines that were first seen to be expressed by leukocytes. The term interleukin describes a variety of polypeptides that act specifically as mediators between leucocytes. However, the name interleukin is something of a relic, since it has been found that interleukins are produced by a wide variety of body cells.
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|• IL1R1||• IL-4R||• IL-2||• IL-7|
|• IL6R||• IL-17A||• IL-15||• IL-21|
Interleukin 1 is the first member of the IL-1 family which is closely linked to the innate immune response. IL-1 affects virtually all cells and organs and is a major pathogenic mediator of autoinflammatory, autoimmune, infectious, and degenerative diseases.
Interleukin 2, also known as T cell growth factor (TCGF), is produced by CD4+ T cells, CD8+ T cells, some B cells and dendritic cells. IL-2 exerts a wide spectrum of effects on the immune system, and it plays crucial roles in regulating both immune activation and homeostasis.
Interleukin 5 was described for the first time as an eosinophil and B-cell growth factor in 1987. In humans, IL-5 is a very selective cytokine as a result of the restricted expression of the interleukin-5 receptor on eosinophils and basophils.
Interleukin 6 is a cytokine not only involved in inflammation and infection responses but also in the regulation of metabolic, regenerative, and neural processes. In classic signaling, IL-6 stimulates target cells via a membrane bound IL-6 receptor, which upon ligand binding associates with the signaling receptor protein gp130.
IL-7 receptor (IL-7R), binding to its cognate ligand IL-7 (interleukin 7), activates multiple pathways that regulate lymphocyte survival, glucose uptake, proliferation and differentiation. IL-7 (interleukin 7) is an essential cytokine for the development and homeostatic maintenance of T and B lymphocytes.
Interleukin 10, first described in 1989 as cytokine synthesis inhibitory factor (CSIF), suppresses immune function by blocking the synthesis of proinflammatory cytokines (e.g., IL-1, IL-6, IFN-γ, and TNF-α) in T cells, monocytes, and macrophages, and by inhibiting the expression of cell surface molecules involved in antigen presentation and costimulation.
IL-12 (interleukin 12) was first described as natural killer stimulating factor in 1989. The heterodimeric cytokine IL-12 consists of a 35-kd light chain (p35 or IL-12A) and 40-kd heavy chain (p40 or IL-12B).
Interleukin 17 is secreted by a variety of innate cells including macrophages, dendritic cells (DC), natural killer, natural killer T, lymphoid tissue inducer and γδ-T cells. IL-17 exerts a host-defensive role in many infectious diseases, and it promotes inflammatory pathology in autoimmunity and other settings.
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|Many cancers arise at sites of infection and inflammation. The IL-1 cytokine family consists of eleven members that play important roles in regulating inflammation.
IL-1 family cytokines activate intracellular signaling pathways by binding to a primary receptor subunit, such as IL-1 RI/IL-1 R1, IL-18 R alpha/IL-1 R5, IL-1 Rrp2/IL-1 R6, or ST2/IL-1 R4, which then recruits an accessory receptor to form the active receptor complex. Signaling cascades triggered by IL-1 alpha, IL-1 beta, IL-18, IL-33, IL-36 alpha, IL-36 beta, or IL-36 gamma activate MAPKs and NF-kappa B, leading to the expression of pro-inflammatory cytokines, chemokines, and secondary mediators of the inflammatory response.
Of note, most intracellular components that participate in the cellular response to IL-1 also mediate responses to other cytokines (IL-18 and IL-33), Toll-like-receptors (TLRs), and many forms of cytotoxic stresses.
|All cytokines in the IL-6 family signal through the common receptor subunit gp130 via the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway.
The first event in activation of the Jak STAT signalling pathway is the ligand-induced homo- or hetero-dimerization of signal-transducing receptor subunits. All IL-6 family cytokines recruit gp130 to their receptor complexes. They either signal via gp130 alone or in combination with LIFR or the recently cloned OSMR, which are all able to activate Jaks and to recruit STAT proteins. IL-6 induces gp130-homodimerization, whereas CNTF, LIF, and CT-1 signal via heterodimerization of gp130 and LIFR.
|All IL-10 family cytokines including IL-10 itself, signal through receptors belonging to the class II cytokine receptor family. These IL-10 family ligands signal through receptor complexes composed of two distinct receptor chains (IL-10RA and IL-10RB) leading primarily to the activation of the Jak–Stat signal transduction pathway. Ligand binding induces oligomerization of receptor subunits.
IL-10 signals via IL-10RA/IL-10RB and results in the phosphorylation of Stat3, a critical transcription factor for the immunosuppressive effect of IL-10. IL-19, IL-20 and IL-24 induced their signaling through the IL-20RA/IL-20RB receptor complex. However, IL-20 and IL-24 preferentially engage with the IL22RA1/IL-20RB receptor complex. IL-22 and IL-26 function via receptor complex consisting of IL-22RA1/IL-10RB or IL-20RA/IL-10RB. Interestingly, IL-20 subfamily can also activate Stat3, but the outcome is different from the activation of IL-10. The molecular mechanisms underlying the diverse effect of Stat3 signaling remain poorly understood.
|IL-12 family cytokines mediate their biological activities by binding Janus kinases (JAKs) associated heterodimeric receptors and activating JAK-STAT signaling pathways.
The IL-12 family receptor chains are used by multiple cytokines. IL-12 signals via IL-12Rβ1 and IL-12Rβ2, whereas IL-23 signals via IL-12Rβ1 and IL-23R. In contrast, IL-27 uses gp130 and IL-27R (WSX-1),whereas IL-35 signals via gp130 and IL-12Rβ2. IL-35 is unusual in that it can also signal via two additional receptor-chain compositions: gp130-gp130 and IL-12Rβ2–lL-12Rβ2 homodimers.
Signaling via all of these receptors is mediated by members of the Jak-STAT family. Jak2 and either Jak1 or Tyk2 seem to mediate phosphorylation of STAT proteins associated with receptors for cytokines of the IL-12 family. IL-12 mediates signaling via p-STAT4, IL-23 mediates signaling via p-STAT3 and p-STAT4, IL-27 mediates signaling via p-STAT1 and p-STAT3, and IL-35 mediates signaling via p-STAT1 and p-STAT4. For IL-35, the formation of a STAT1-STAT4 heterodimer is required for transcription of Ebi3 and Il12a but is partially dispensable for the suppression of T cells.
|IL-17 family has been shown to activate many common downstream signaling pathways, including NF-κB, the MAPKs (mitogen-activated protein kinases) JNK (c-Jun N-terminal kinase), p38 and ERK (extracellular-signalregulated kinase), C/EBPs (CCAAT/enhancer-binding proteins), PI3K (phosphoinositide 3-kinase) and JAK (Janus kinase)/STATs.
All of the IL-17 receptors recruit Act1 as an adaptor molecule for downstream signaling. IL-17A and IL-17F signals through the IL-17RA-RC complex, triggering TRAF6-dependent target gene transcription and TRAF6-independent IKKi-dependent mRNA stabilization, both of which are important for host defense and contributes to the pathogenesis of autoimmune diseases and cancer.
|Signaling of common gamma‑chain (γc) cytokines is triggered by hetero-dimerization of a proprietary cytokine receptor with the shared γc chain. Hetero-dimerization brings the intracellular domains of the receptors into close physical proximity, and thus leads to trans-phosphorylation and activation of receptor associated protein tyrosine kinases.
Common gamma-chain (γc) family cytokines all signal through the JAK–STAT (signal transducer and activator of transcription) pathway. IL‑2, IL‑7, IL‑9 and IL‑15 mainly activate STAT5A and STAT5B (together referred to here as STAT5), whereas IL‑4 generally activates STAT6 and IL‑21 mainly activates STAT3. The activation of different STAT proteins could help to explain the different effects of these cytokines.