Interleukin-10 (IL-10) signals through a receptor complex consisting of two IL-10 receptor-1 (IL-10R1) and two IL-10 receptor 2 (IL-10R2). Both subunits belong to the class II cytokine receptor family. IL-10R1 is expressed on haematopoietic cells (such as T, B, NK, mast, and dendritic cells) whilst the IL-10R2 subunit is expressed ubiquitously. Assembly of the cell surface IL-10 receptor (IL-10R) complex is the first step in initiating IL-10 signaling pathways that regulate intestinal inflammation, viral persistence, and even tumor surveillance.
IL-10 receptor 1 (IL-10R1, also referred to as IL-10Rα) 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.
While IL-10R2 is ubiquitously expressed and is unable to bind IL-10 alone, the expression of IL-10R1 determines cellular responsiveness. IL-10 receptor 1 (IL-10R1) has a central role in IL-10 binding and signaling. It is responsible for the initial binding of IL-10, has a substantial role in stabilizing the IL-10/IL-10R1/ IL-10R2 complex, and interacts with specific transcription factors.
The ECD of IL-10 receptor 2 (IL-10R2, also referred to as IL-10Rβ) is about the same length as IL-10 receptor 1 (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 with IL-10, while IL-10R2 is a low affinity shared receptor that participates in receptor complexes with other class II cytokine family members including IL22, IL26, and INFλ, etc. Earlier studies have suggested that IL10Rβ has almost no role in IL10-binding, its main role is to recruit the downstream signaling kinases. Some recent studies have also found that upon binding to IL10, IL10Rα induces a conformational change in IL10Rβ, permitting IL10Rβ to also bind IL10.
Interleukin-10 (IL-10) is an anti-inflammatory cytokine with important immunoregulatory functions. It is a cytokine with potent anti-inflammatory properties, repressing the expression of inflammatory cytokines such as TNF-Alpha, IL-6 and IL-1 by activated macrophages IL-10 is a pleiotropic cytokine with important immunoregulatory functions. Its actions influence activities of many of the cell-types in the immune system.
The sequence of receptor assembly is initiated by IL10 binding to IL10Rα. This complex then binds IL10Rβ forming a heterotetramer, permitting the assembly of the signaling complex. Once the complex is assembled, tyrosine kinases Jak1 and Tyk2 that are constitutively associated with IL10Rα and IL10Rβ, respectively, are activated and phosphorylate specific tyrosine residues in the intracellular domain of IL10Rα. Phosphorylation of the receptor leads to the recruitment of signal transducer and activator of transcription 3 (STAT3).
Following their recruitment, JAK1 and TYK2 phosphorylate STAT3.
Then, STAT3 forms a homodimer and undergoes nuclear translocation where it binds to STAT3-binding elements of IL10-responsive genes and drives expression of anti-inflammatory mediators that block various inflammatory pathways.
IL-10/IL10R deficiency is severe, life-threatening, and resistant to conventional anti-inflammatory drugs. It can cause severe earlyonset enterocolitis and are difficult to control with conventional immunosuppressive therapies. Thus, hematopoietic stem cell transplantation (HSCT) has been referred to and proved a curative therapeutic approach that induced remission in several patients.
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