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IL-10 / Interleukin 10
IL-10 / Interleukin 10, a type of interleukins, is a type Ⅱcytokine and the 'founding' member of a family of cytokines that include IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29. All of these cytokines have similar intron–exon genomic organization, bind to receptors with similar structures and in some cases shared components, and all activate Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathways. Despite these commonalities, the cytokines in this family have very different biological activities, which are largely determined by the cells producing the cytokine, the cells responding to them, and the immune environment in which they are released. The four major T-cell sources of IL-10 are T-helper type 2 (Th2) cells, subsets of regulatory T cells designated Tr1, Th1, and Th17 cells. CD8+ T cells also produce IL-10.
Other important producers of IL-10 include monocytes and appropriately stimulated macrophages, as well as some subsets of dendritic cells (DCs). Human B cells are also a potentially important source of IL-10, as are some granulocytes, including eosinophils and mast cells. Non-immune cell sources of IL-10 include keratinocytes, epithelial cells, and even tumor cells. The main biological function of IL-10 seems to be the limitation and termination of inflammatory responses and the regulation of differentiation and proliferation of several immune cells such as T cells, B cells, natural killer cells, antigen-presenting cells, mast cells, and granulocytes. However, very recent data suggest IL-10 also mediates immunostimulatory properties that help to eliminate infectious and noninfectious particles with limited inflammation. Numerous investigations, including expression analyses in patients, in vitro and animal experiments suggest a major impact of IL-10 in inflammatory, malignant, and autoimmune diseases. So IL-10 overexpression was found in certain tumors as melanoma and several lymphomas and is considered to promote further tumor development. Systemic IL-10 release is a powerful tool of the central nervous system to prevent hyperinflammatory processes by activation of the neuro-endocrine axis following acute stress reactions. In contrast, a relative IL-10 deficiency has been observed and is regarded to be of pathophysiological relevance in certain inflammatory disorders characterized by a type 1 cytokine pattern such as psoriasis. Recombinant human IL-10 has been produced and is currently being tested in clinical trials. This includes rheumatoid arthritis, inflammatory bowel disease, psoriasis, organ transplantation, and chronic hepatitis C. The results are heterogeneous. They give new insight into the immunobiology of IL-10 and suggest that the IL-10/IL-10 receptor system may become a new therapeutic target.
IL-10 Family Ligand
IL-10 Family Receptor
IL-10 Family Signaling Related Molecules
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IL-10 Receptor and IL-10 Signaling
As for IL-10, all the receptors of the new molecules from the IL-10 family known so far belong to the cytokine receptor family type 2 (CRF2). They are generally transmembrane glycoproteins whose extracellular domains consist of about 210 amino acids comprising two tandem fibronectin type III domains and having several conserved amino acid positions important for the secondary structure. More recently, it has been discovered that some of the human IL-10 homologs share single receptor chains and even whole receptor complexes. IL-10 signals through a two-receptor complex consisting of two copies each of IL-10 receptor 1 (IL-10R1) and IL-10R2. IL-10R1 binds IL-10 with a relatively high affinity (50–200 pM), and the recruitment of IL-10R2 to the receptor complex makes only a marginal contribution to ligand binding. However, the engagement of this second receptor to the complex enables signal transduction following ligand binding. Thus, the functional receptor consists of a dimer of heterodimers of IL-10R1 and IL-10R2. Most hematopoietic cells constitutively express low levels of IL-10R1, and receptor expression can often be dramatically upregulated by various stimuli. Non-hematopoietic cells, such as fibroblasts and epithelial cells, can also respond to stimuli by upregulating IL-10R1. The IL-10R2 is expressed on most cells, and therefore a large number of diverse cells have the ability to bind to and consume IL-10. This represents a problem for the therapeutic administration of recombinant IL-10 (rIL-10), because much of the cytokine can be diverted to non-immune cells thereby diminishing the effective dosage administered. This effect almost certainly contributed to the marginal success of some of the early clinical trials in which IL-10 was administered subcutaneously at sites distal to the sites of inflammation.
The binding of IL-10 to the receptor complex activates the Janus tyrosine kinases, JAK1 and Tyk2, associated with IL-10R1 and IL-10R2, respectively, to phosphorylate the cytoplasmic tails of the receptors. This results in the recruitment of STAT3 to the IL-10R1. The site of STAT3 recruitment is conserved between the human and murine receptor and is shared by other STAT3-recruiting receptors, including gp130, IL-20R1, and IL-22R1. The homodimerization of STAT3 results in its release from the receptor and translocation of the STAT homodimer into the nucleus, where it binds to STAT-binding elements in the promoters of various genes. One of these genes is IL-10 itself, which is positively regulated by STAT3. STAT3 also activates the suppressor of cytokine signaling 3 (SOCS3), which controls the quality and quantity of STAT activation. The phosphoinositide 3-kinase (PI3K) pathway is also activated by IL-10. Furthermore, the STAT3-dependent silencing of many cytokine genes in IL-10-treated macrophages is in stark contrast to the enhanced production of genes such as IL-1 receptor antagonist in these same cells. Several groups have demonstrated that IL-10 treatment results in diminished nuclear factor-κB (NF-κB) activation in response to a variety of different stimulialthough this effect may be cell-type specific. This may occur through the suppression of inhibitor of NF-κB (IκB) kinase (IKK) activity by IL-10, resulting in the retention of NF-κB subunits in the cytoplasm.
References
- Shankar Subramanian Iyer et al. (2012) Role of Interleukin 10 Transcriptional Regulation in Inflammation and Autoimmune Disease. Crit Rev Immunol. 32(1): 23–63.
- David M. Mosser et al. (2008) Interleukin-10: new perspectives on an old cytokine. Immunol Rev. 226: 205–218.
- K. Asadullah. et al. (2009) Interleukin-10 Therapy—Review of a New Approach. Pharmacol Rev. 55:241–269.
- Simone M. et al. (2005) Interleukin-10 and the immune response against cancer: a counterpoint. JLB. 78(5): 1043–1051.
- Zdanov, A. et al. (1996) Crystal structure of human interleukin-10 at 1.6 A resolution and a model of a complex with its soluble receptor. Protein Sci. 5: 1955-1962.
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