All members of the IL-10 family have the following features: clustering of their encoding genes, similar genomic structures, similar primary and secondary protein structures, and utilization of similar receptor complexes.
The amino acid (aa) identity between the members of the IL-10 family is approximately 9-40% whereby characteristic aa positions are conserved. Despite the relatively low sequence identity, all IL-10 family members show a strikingly similar secondary structure.
Despite their structural relation and their use of similar or partly identical receptors, members of the IL-10 family possess different biological functions.
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IL-10 family ligands can be classified into three subgroups based primarily on their biological functions. The first group contains only IL-10 itself. The second group, namely IL-20 subfamily ligands, is composed of IL-19, IL-20, IL-22, IL-24, and IL-26. The last group is the type III IFN group (or IFN λs), which contains the closely related cytokines IL-28A, IL-28B, and IL-29.
The pleiotropic activities of IL-10 family members are mediated by specific cell surface receptor complexes that each consist of an R1 chain and an R2 chain, both being members of the class II cytokine receptor family (CRF2).
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.