Key Points
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Type II cytokine receptors consist of 1 soluble and 11 transmembrane proteins that have 20–30% amino-acid identity in their extracellular domain.
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The ligands have a common structure with six α-helices, organized as monomers or homodimers, and have 20–30% amino-acid identity.
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Receptors associate as heterodimers including common chains and a high level of complexity in cytokine–receptor interactions results from the fact that one particular cytokine can bind to two different receptor complexes, and that one particular receptor complex can bind several cytokines.
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Type I interferons (IFNs), IL-28 and IL-29 have important roles in antiviral responses through the activation of signal transducer and activator of transcription 2 (STAT2).
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Inflammatory responses are modulated by members of this family; IL-10 and IFN-γ have anti- and pro-inflammatory activities, respectively; IL-22 induces the production of acute-phase reactants and IL-20 regulates the proliferation of keratinocytes.
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Antitumour activities have been described for type I IFNs and IL-24 delivered by adenoviruses through an unknown mechanism, potentially independent from IL-24 receptor activation.
Abstract
Class II cytokine receptors were originally defined on the basis of sequence homologies in the extracellular domains of receptors for interferons (IFNs) and interleukin-10 (IL-10), and the ligands, known as class II cytokines, also have a common structure. More recently, a series of new receptors and cytokines that belong to this family have been discovered. The therapeutic potential of the 'old' members of this family, IFNs and IL-10, is recognized in the clinic, and the existence of structurally related molecules is raising expectations for additional clinical applications. In this review, I discuss both structural and biological data that are emerging about this family of receptors and ligands, to highlight the potential applications of modulating the activity of these cytokines.
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Glossary
- CDNA SUBTRACTION CLONING
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A method of cDNA cloning aimed to identify genes that are expressed specifically in a given tissue or after a particular stimulation.
- FIBRONECTIN DOMAINS
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Fibronectin is an extracellular multiadhesive protein that binds to other matrix components, fibrin and cell-surface receptors of the integrin family. Fibronectin is composed of three types of repeating amino-acid sequences. The type III fibronectin domain is a 100 amino acid repeated domain that is involved in the binding of integrins.
- EPSTEIN–BARR VIRUS
-
(EBV). A double-stranded DNA virus of the herpes-virus family, which is the aetiologic agent of infectious mononucleosis and is associated with some B-cell malignant tumours and nasopharyngeal carcinoma. EBV infects B cells and some epithelial cells by specifically binding to complement receptor 2 (CD21).
- ACUTE-PHASE REACTANTS
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(APRs). APRs consist of plasma proteins the expression of which is up- or downregulated during inflammation as the result of the endocrine activity of cytokines. Most APRs are produced by the liver and include components of the complement pathways, factors of the coagulation system, proteinase inhibitors, metal-binding proteins and other proteins involved in various infection-associated functions.
- PSORIASIS
-
A chronic skin disease that affects 1–2% of the population, in which the skin becomes inflamed, producing red, thickened areas with silvery scales, most often on the scalp, elbows, knees and lower back. Recent evidence points to a T-cell-mediated pathogenesis in genetically susceptible individuals, resulting in inflammation and epidermal hyperplasia.
- RNA-DEPENDENT PROTEIN KINASE
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(PKR). PKR is a protein kinase that requires double-stranded RNA to exert its activity. This is supplied by virus RNA, which frequently loops back on itself to form double-stranded regions. One of the substrates of PKR is translation initiation factor 2 (IF2) — a factor involved in protein synthesis. IF2 is essential for the initiation complex of protein synthesis, but loses its activity after phosphorylation.
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Renauld, JC. Class II cytokine receptors and their ligands: Key antiviral and inflammatory modulators. Nat Rev Immunol 3, 667–676 (2003). https://doi.org/10.1038/nri1153
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DOI: https://doi.org/10.1038/nri1153
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