The Interleukin-10 family (IL-10 family) is a group of 6 cytokines, which plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults. In addition to IL-10, it includes IL-19, IL-20, IL-22, IL-24 and IL-26. Some sources also include the interferons IL-28 and IL-29.
Members of IL-10 Family
Table 1. IL-10 family related products
|IL-10 Family Ligands||IL10||IL19||IL20|
|IL-10 Family Receptors||IL10RA||IL10RB||IL20RA|
Interleukin 10 (IL-10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory cytokine. In humans, IL-10 is encoded by the IL10 gene, which is located on chromosome 1 and comprises 5 exons, and is primarily produced by monocytes and, to a lesser extent, lymphocytes, namely type 2 T helper cells (TH2), mast cells, CD4+CD25+Foxp3+ regulatory T cells, and in a certain subset of activated T cells and B cells. IL-10 signals through a receptor complex consisting of two IL-10 receptor-1 and two IL-10 receptor-2 proteins. Consequently, the functional receptor consists of four IL-10 receptor molecules. IL-10 binding induces STAT3 signaling via the phosphorylation of the cytoplasmic tails of IL-10 receptor 1 + IL-10 receptor 2 by JAK1 and Tyk2 respectively.
IL-10 induction involves ERK1/2, p38 and NF-κB signaling and transcriptional activation via promoter binding of the transcription factors NF-κB and AP-1. IL-10 may autoregulate its expression via a negative feed-back loop involving autocrine stimulation of the IL-10 receptor and inhibition of the p38 signaling pathway. Additionally, IL-10 expression is extensively regulated at the post-transcriptional level, which may involve control of mRNA stability via AU-rich elements and by microRNAs such as let-7 or miR-106.
Figure 1. IL-10 protein
Interleukin 19 (IL19) is a protein that in humans is encoded by the IL19 gene. The protein encoded by this gene is a cytokine that belongs to the IL-10 cytokine subfamily. It signals through the same cell surface receptor (IL-20R) that is used by IL-20 and IL-24. The IL-19 gene is expressed in resting monocytes and B cells. It is up-regulated in monocytes following stimulation with granulocyte-macrophage colony-stimulating factor (GM-CSF), lipopolysaccharide, or Pam3CSK4. It can bind the interleukin-20 receptor complex and lead to the activation of the signal transducer and activator of transcription 3 (STAT3). A similar cytokine in mouse is reported to up-regulate the expression of IL6 and TNF-alpha and induce apoptosis, which suggests a role of this cytokine in inflammatory responses. Alternatively spliced transcript variants encoding the distinct isoforms have been described.
Figure 2. IL-19 protein
Interleukin-20 (IL-20) is a protein belonging to the IL-10 family of cytokines. It is a protein that in humans is encoded by the IL20 gene. The protein encoded by this gene is a cytokine structurally related to interleukin 10 (IL-10). This cytokine has been shown to transduce its signal through signal transducer and activator of transcription 3 (STAT3) in keratinocytes. A specific receptor for this cytokine is found to be expressed in skin and upregulated dramatically in psoriatic skin, suggesting a role for this protein in epidermal function and psoriasis.
IL-22 is an α-helical cytokine. IL-22 binds to a heterodimeric cell surface receptor composed of IL-10R2 and IL-22R1 subunits. IL-22R is expressed on tissue cells, and it is absent on immune cells. Crystallization is possible if the N-linked glycosylation sites are removed in mutants of IL-22 bound with high-affinity cell-surface receptor sIL-22R1. The crystallographic asymmetric unit contained two IL-22-sIL-22R1 complexes. IL-22, signals through the interferon receptor-related proteins CRF2-4 and IL-22R. It forms cell surface complexes with IL-22R1 and IL-10R2 chains resulting in signal transduction through receptor, IL-10R2. The IL-22/IL-22R1/IL-10R2 complex activates intracellular kinases (JAK1, Tyk2, and MAP kinases) and transcription factors, especially STAT3. It can induce IL-20 and IL-24 signaling when IL-22R1 pairs with IL-20R2.
Interleukin 24 (IL-24) is a protein that in humans is encoded by the IL24 gene. IL-24 is a cytokine belonging to the IL-10 family of cytokines that signals through two heterodimeric receptors: IL-20R1/IL-20R2 and IL-22R1/IL-20R2. This interleukin is also known as melanoma differentiation-associated 7 (mda-7) due to its discovery as a tumour suppressing protein. IL-24 appears to control in cell survival and proliferation by inducing rapid activation of particular transcription factors called STAT1 and STAT3. This cytokine is predominantly released by activated monocytes, macrophages and T helper 2 (Th2) cells and acts on non-haematopoietic tissues such as skin, lung and reproductive tissues.
IL-26 is a 171-amino acid protein, which is similar in amino acid sequence to interleukin 10. It was originally called AK155 and is composed of a signal sequence, 6 helices, and 4 conserved cysteine residues. IL-26 is expressed in certain herpesvirus-transformed T cells but not in primary stimulated T cells. IL-26 signals through a receptor complex comprising two distinct proteins called IL-20 receptor 1 and IL-10 receptor 2. By signaling through this receptor complex, IL-26 induces rapid phosphorylation of the transcription factors STAT1 and STAT3, which enhance IL-10 and IL-8 secretion and as expression of the CD54 molecule on the surface of epithelial cells.
IL-10 is a cytokine with multiple, pleiotropic effects in immunoregulation and inflammation. It downregulates the expression of Th1 cytokines, MHC class II antigens, and co-stimulatory molecules on macrophages. It also enhances B cell survival, proliferation, and antibody production. IL-10 can block NF-κB activity, and is involved in the regulation of the JAK-STAT signaling pathway. Discovered in 1991 IL-10 was initially reported to suppress cytokine secretion, antigen presentation and CD4+ T cell activation. Further investigation has shown that IL-10 predominantly inhibits lipopolysaccharide (LPS) and bacterial product mediated induction of the pro-inflammatory cytokines TNFα, IL-1β, IL-12, and IFNγ secretion from Toll-Like Receptor (TLR) triggered myeloid lineage cells.
IL-20 is produced by activated keratinocytes and monocytes and transmits an intracellular signal through two distinct cell-surface receptor complexes on keratinocytes and other epithelial cells. IL-20 regulates proliferation and differentiation of keratinocytes during inflammation, particularly inflammation associated with the skin. In addition, IL-20 also causes cell expansion of multipotential hematopoietic progenitor cells.
IL-22 is produced by activated NK and T cells and initiates innate immune responses against bacterial pathogens especially in epithelial cells such as respiratory and gut epithelial cells. IL-22 along with IL-17 is rapidly produced by splenic LTi-like cells and also produced by Th17 cells and likely plays a role in the coordinated response of both adaptive innate immune systems, autoimmunity and tissue regeneration.
IL-26, a human TH17 cell–derived cytokine, is a cationic amphipathic protein that kills extracellular bacteria via membrane-pore formation. Furthermore, TH17 cell–derived IL-26 forms complexes with bacterial DNA and self-DNA released by dying bacteria and host cells. The IL-26–DNA complexes trigger the production of type I interferon by plasmacytoid dendritic cells via activation of Toll-like receptor 9, but independently of the IL-26 receptor.
Figure 3. Proposed cellular sources and actions of IL-26 in human organs.
(Fibro = Fibroblasts; Macro = macrophages; Neutro = neutrophils)
Role in disease
IL-10 is linked to the myokines, as exercise provokes an increase in circulating levels of IL-1ra, IL-10, and sTNF-R, suggesting that physical exercise fosters an environment of anti-inflammatory cytokines. Lower levels of IL-10 have been observed in individuals diagnosed with multiple sclerosis when compared to healthy individuals. Due to a decrease in IL-10 levels, TNFα levels are not regulated effectively as IL-10 regulates the TNF-α-converting enzyme. As a result, TNFα levels rise and result in inflammation.
Patients with Crohn's disease react favorably towards treatment with recombinant interleukin-10-producing bacteria, demonstrating the importance of IL-10 for counteracting the hyperactive immune response in the human body. A Phase I immunoncology clinical trial is currently being conducted to assess the therapeutic capacity of PEGylated recombinant human IL-10 (PEG-rHuIL-10, AM0010). Consistent with preclinical immunoncology data, investigators report substantial anti-tumor efficacy.
Anti-IL-20 monoclonal antibodies have been researched as clinical candidates for the treatment or prevention of psoriasis, rheumatoid arthritis, atherosclerosis, osteoporosis, and stroke.
IL-22 can contribute to immune disease through the stimulation of inflammatory responses, S100s and defensins. IL-22 also promotes hepatocyte survival in the liver and epithelial cells in the lung and gut similar to IL-10. In some contexts, the pro-inflammatory versus tissue-protective functions of IL-22 are regulated by the often co-expressed cytokine IL-17A.
IL-24 performs important roles in wound healing, arthritis, psoriasis and cancer. Several studies have shown that cell death occurs in cancer cells/cell lines following exposure to IL-24.
Interleukin 26 (IL-26), is a natural human antimicrobial that promotes immune sensing of bacterial and host cell death.