IL-10 Family Cytokines

IL-10 Family Cytokines, Receptors, and Signaling Pathways

IL-10 Family Cytokines

The IL-10 family of cytokines consists of six members, IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, and is sometimes extended to include the more distantly related type III interferons, IL-28A, IL-28B, and IL-29. Members of the IL-10 cytokine family are grouped primarily based on structural similarities, utilization of common receptor subunits, and activation of similar downstream signaling pathways. All members of the IL-10 family have six or seven alpha helices connected by loops, with four of the helices compacted into the classic four-helix bundle structure formed by all helical cytokines. The alpha helices form a hydrophobic core that is stabilized by one to three disulfide bridges. With the exception of IL-10 and IL-26, IL-10 family cytokines function as monomers. IL-10 forms a noncovalently associated homodimer, although dimer formation is not required for its downstream functions.  Likewise, IL-26 has also been reported to be expressed as a homodimer and is predicted to exist in a multimeric form as well.  

IL-10 Family Receptors

The IL-10 family cytokines are ligands for receptors belonging to the class II cytokine receptor family. Class II cytokine receptors consist of one to four receptor chains that have an extracellular cytokine receptor homology domain with two tandem, fibronectin type III domains that each contain one cysteine pair in the fibronectin fold. Monomeric IL-10 family cytokines exert their effects through heterodimeric receptor complexes consisting of one long, alpha chain transmembrane subunit (R1) paired with one short, beta chain transmembrane subunit (R2). The homodimeric IL-10 cyokine signals through a heterotetrameric receptor complex composed of two alpha chain subunits and two beta chain subunits. Receptors for the IL-10 family cytokines contain one of four different alpha chain subunits, IL-10 R alpha/IL-10 R1, IL-20 R alpha/IL-20 R1, IL-22 R alpha 1, or IL-28 R alpha/IFN-lambda R1, coupled with one of two different beta chain subunits, IL-10 R beta/IL-10 R2 or IL-20 R beta/IL-20 R2. Significantly, all IL-10 family receptors share at least one receptor subunit with another receptor in the family, and some IL-10 family cytokines can signal through more than one receptor complex. The IL-10 receptor complex consists of two IL-10 R alpha/IL-10 R1 subunits and two IL-10 R beta/IL-10 R2 subunits. IL-10 initially binds to the high-affinity alpha subunit, which subsequently recruits the IL-10 R beta/IL-10 R2 subunit to form the active receptor complex. Similarly, IL-22 and IL-26 initially bind to IL-22 R alpha 1 or IL-20 R alpha/IL-20 R1, respectively, and subsequently recruit IL-10 R beta/IL-10 R2 to form active receptor complexes. Type III IFNs also signal through a complex that contains IL-10 R beta/IL-10 R2, but in this case, it is coupled with IL-28 R alpha 1/IFN-lambda R1.  In contrast, IL-19, IL-20, and IL-24 signal through a receptor complex consisting of IL-20 R alpha/IL-20 R1 and IL-20 R beta/IL-20 R2, known as the type I IL-20 receptor complex. Additionally, IL-20 and IL-24 can bind with similar affinity and signal through another receptor complex known as the type II IL-20 receptor complex, which consists of IL-22 R alpha 1 and IL-20 R beta/IL-20 R2. Unlike the cytokines whose receptors contain the IL-10 R beta/IL-10 R2 subunit, cytokines whose receptors contain the IL-20 R beta/IL-20 R2 subunit initially interact with this subunit and then recruit one of the alpha chain receptor subunits to form a ternary receptor complex.

IL-10 Family Signaling

Formation of the active IL-10 family receptor complexes results in activation of Jak-STAT signaling. Following phosphorylation of the intracellular domain of the alpha chain receptor subunit by the Jak family kinases, STAT proteins are recruited to the receptor and subsequently phosphorylated by Jak1, Jak2, or Tyk2. STAT protein phosphorylation leads to their dimerization and translocation to the nucleus, where they can affect the expression of multiple target genes. Signaling by IL-10 family cytokines primarily activates STAT3, but several IL-10 family cytokines have also been shown to activate STAT1 and STAT5 at higher concentrations. In addition to Jak-STAT signaling, IL-10 and IL-22 also activate the PI 3-kinase/Akt signaling pathway, and IL-20 and IL-22 have been shown to activate JNK, ERK, and p38 MAPK signaling in multiple different cell types.

Functions of IL-10 Family Cytokines

The specificity of the responses to IL-10 family cytokines is regulated through limited expression of the alpha chain receptor subunits. While IL-10 R beta/IL-10 R2 is constitutively expressed on most cell types, expression of IL-10 R alpha/IL-10 R1, IL-20 R alpha/IL-20 R1, and IL-22 R alpha 1 is more restricted. IL-10 R alpha/IL-10 R1 is primarily expressed by hematopoietic cells. In contrast, expression of IL-20 R alpha/IL-20 R1 is primarily restricted to epithelial cells, and IL-22 R alpha 1 expression is primarily limited to epithelial and stromal cells. As a result, hematopoietic cells are the primary targets of IL-10, while other IL-10 family cytokines are involved in regulating the activities of epithelial and stromal cells.

IL-10 plays a critical role in down regulating immune responses and preventing excessive inflammation. IL-10 inhibits the antigen-presenting capabilities of dendritic cells, monocytes, and macrophages, and decreases their production of pro-inflammatory molecules, while increasing their production of anti-inflammatory mediators and their phagocytic functions. IL-10 can also act on eosinophils, mast cells, and neutrophils to inhibit their production of pro-inflammatory mediators. Additionally, IL-10 can down regulate Th1 and Th17 cell-mediated immune responses by inhibiting T cell proliferation, down regulating the expression of co-stimulatory molecules and suppressing cytokine secretion, while also promoting the survival and maintenance of FoxP3⁺ regulatory T cells. Significantly, it has also been found that under certain conditions, IL-10 can have immune stimulatory effects on B cells, natural killer cells, and T cells.

Unlike IL-10, the other IL-10 family cytokines primarily act on epithelial cells and stromal cells. IL-19, IL-20, IL-22, IL-24, and IL-26 have been grouped into a subfamily known as the IL-20 family cytokines due to similarities in their receptors, target cells, and functions. IL-20 family cytokines are involved in regulating the activities of epithelial cells to maintain or restore tissue homeostasis following infection or inflammation. They induce epithelial cell expression of anti-microbial proteins, pro-inflammatory mediators, and chemokines to promote immune cell recruitment to sites of inflammation. In addition, IL-19, IL-22, and IL-24 have been shown to be involved in skin healing, while IL-20, IL-22, and IL-24 have been shown to mediate protective effects in keratinocytes. They not only promote keratinocyte proliferation and migration, but they also promote the expression of anti-microbial proteins. Multiple studies suggest that elevated expression of IL-19, IL-20, IL-22, IL-24, and IL-26 may be associated with the pathogenesis of chronic inflammatory and autoimmune diseases, including psoriasis, inflammatory bowel disease, and rheumatoid arthritis.

Bio-Techne offers a wide selection of products for investigating the functions of IL-10 family cytokines and the signaling pathways that they activate. Our portfolio includes R&D Systems™ bioactive recombinant proteins, single and multianalyte immunoassays in several different formats, and antibodies qualified for one or more of the following applications: blocking/neutralization, immunohistochemistry, immunoprecipitation, Western blotting, and flow cytometry.