IL-10 receptor family belongs to the class II cytokine receptor family (CRF2), due to the presence of two particular disulfide bridges and the absence of the so-called "WSXWS" motif in the C-terminal part of the extracellular domain. The cognate ligands for the class II cytokine receptors are thus referred to as the class II cytokines.
All functional IL-10 receptor complexes are heterodimers consisted of two types of chains: alpha subunit and beta subunit. In each signaling receptor complex, alpha subunit is the ligand-binding one and beta subunit is the accessory signaling subunit.
Below will briefly discuss structures and functions of IL-10 receptor family, including IL-10 receptor complex, IL-20 receptor complex, IL-22 receptor complex, and IFN lambda receptor 1/IL-28R1.
The IL-10 receptor complex on cells is composed of four transmembrane polypeptides: two chains of IL-10R1 that bind ligand and two chains of IL-10R2 that initiate signal transduction. IL-10R2 is the accessory signaling subunit. Both IL-10R1 and IL-10R2, belong to the Class II cytokine receptor family.
IL-10R1 is an ~80,000 kDa protein with an extracellular ligand binding domain (ECD) of 227 residues, a transmembrane helix of 21 residues, and an intracellular domain (ICD) of 322 amino acids.
The ECD of IL-10R2 is about the same length as IL-10R1, consisting of 201 residues. However, the ICD of IL-10R2 consists of only 83 residues. The IL-10R1 ECD forms specific high affinity interactions (KD = 50-200pM) with IL-10, while IL-10R2 is a low affinity (~mM) shared receptor that participates in receptor complexes with other class 2 cytokine family members.
Owing to its structural homology to the IFN-γ receptor complex, shown to be preassembled, the IL-10 receptor complex was predicted to be preassembled as well.
It was shown that IL-19, IL-20 and IL-24 signal through the same two chains, IL-20R1 and IL-20R2. In addition, IL-20 and IL-24 signal through the pair IL-22R1/IL-20R2 and IL-22 uses IL-22R1 and IL-10R2.
IL-20R2 is a high-affinity receptor chain in the case of IL-19 and IL-20. It binds the ligand first, forming a binding site for the long receptor chain IL-20R1, which binds the next. It is very likely that IL-24 also binds to IL-20R2 first. Since the three-dimensional structure of these cytokines is similar to the structure of one domain of IL-10 and all receptors belong to the same family, it is reasonable to assume that receptor binding sites should be also somewhat similar.
Monkey COS cells expressing IL-22R1 are sensitive to IL-22, whereas in Chinese hamster cells both chains IL-22R1 and IL-10R2 must be coexpressed to sustain IL-22 signaling through signal transducer and activator of transcription (STAT) activation. This implies that a functional IL-22 receptor complex, which comprises of two receptor chains: IL-22R1 (CRF2-9, cytokine receptor family class 2 member 9) and IL-10R2 (CRF2-4, the second chain of the IL-10 receptor complex).
When IL-10R2 and IL-22R1 were coexpressed in hamster cells, the cells become responsive to IL-22. IL-22 also has a natural soluble receptor or IL-22 binding protein (IL-22BP), which is also a type II receptor, but it lacks both the transmembrane and intracellular domains and binds IL-22 on its own.
In addition, anti-IL-10R2 antibody completely blocked IL-22-mediated expression of serum amyloid A and luciferase reporter activity in HepG2 cells.
IL-28 and IL-29, type III IFN/Interferon, induce similar downstream biological effects as type I IFNs. Structurally, however, type III IFNs are more closely related to IL-10 family cytokines, especially IL-22.
Indeed, IL-28A, IL-28B, and IL-29 also signal through the same IL-10R2 chain, paired with their unique IL-28R1 as the alpha chain. IL-28R1 are preferentially expressed on various tissue epithelial cells and fibroblasts.
IL-28RA is required for the enhanced antiviral activity induced by TLR3 and TLR9 agonists. Mice lacking IL-28RA and IFN-αR are much more susceptible to highly attenuated influenza A viruses that are usually nonpathogenic, suggesting that type I and type III IFNs cooperate in host defense against influenza infections.
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