Interleukin 10

Interleukin-10 (IL-10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory is_associated_with::cytokine. In humans, IL-10 is encoded by the IL10 gene. 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 signalling via the phosphorylation of the cytoplasmic tails of IL-10 receptor 1 + IL-10 receptor 2 by JAK1 and Tyk2 respectively.

Gene and protein structure
The IL-10 protein is a homodimer; each of its subunits is 178-amino-acid long.

IL-10 is classified as a class-2 cytokine, a set of cytokines including IL-19, IL-20, IL-22, IL-24 (Mda-7), and IL-26, interferons (IFN-alpha, -beta, -epsilon, -kappa, -omega, -delta, -tau, and -gamma) and interferon-like molecules (limitin, IL-28A, IL-28B, and IL-29).

Expression and synthesis
In humans, IL-10 is encoded by the IL10 gene, which is located on chromosome 1 and comprises 5 is_associated_with::exons, and is primarily produced by is_associated_with::monocytes and, to a lesser extent, is_associated_with::lymphocytes, namely type 2 is_associated_with::T helper cells (TH2), mastocytes, CD4+CD25+Foxp3+ is_associated_with::regulatory T cells, and in a certain subset of activated is_associated_with::T cells and is_associated_with::B cells. IL-10 can be produced by monocytes upon PD-1 triggering in these cells. The expression of IL-10 is minimal in unstimulated tissues and seems to require triggering by commensal or pathogenic flora. IL-10 expression is tightly regulated at the transcriptional and post-transcriptional level. Extensive IL-10 locus remodeling is observed in monocytes upon stimulation of is_associated_with::TLR or is_associated_with::Fc receptor pathways. IL-10 induction involves ERK1/2, p38 and NF-κB signalling 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 is_associated_with::microRNAs such as let-7 or miR-106.

IL-10 is released by is_associated_with::cytotoxic T-cells to inhibit the action of is_associated_with::NK cells during the immune response to viral is_associated_with::infection.

Function
IL-10 is a cytokine with multiple, is_associated_with::pleiotropic, effects in immunoregulation and inflammation. It downregulates the expression of Th1 cytokines, MHC class II antigens, and co-stimulatory molecules on is_associated_with::macrophages. It also enhances B cell survival, proliferation, and antibody production. IL-10 can block is_associated_with::NF-κB activity, and is involved in the regulation of the is_associated_with::JAK-STAT signaling pathway.

Role in disease
Knockout studies in mice suggested the function of this cytokine as an essential immunoregulator in the intestinal tract. and, indeed, patients with is_associated_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 study in mice has shown that IL-10 is also produced by is_associated_with::mast cells, counteracting the inflammatory effect that these cells have at the site of an is_associated_with::allergic reaction.

IL-10 is capable of inhibiting synthesis of pro-inflammatory cytokines such as IFN-γ, IL-2, IL-3, TNFα and is_associated_with::GM-CSF made by cells such as is_associated_with::macrophages and regulatory T-cells. It also displays a potent ability to suppress the antigen-presentation capacity of antigen presenting cells; however, it is also stimulatory towards certain T cells (Th2) and mast cells and stimulates B cell maturation and antibody production.

IL-10 checks the inducible form of Cyclo-oxygenase, Cyclo-oxygenase-2 (COX-2). Lack of IL-10 has been shown to cause COX activation and resultant Thromboxane receptor activation to cause vascular endothelial and cardiac dysfunctions in mice. Interleukin 10 knockout frail mice develop cardiac and vascular dysfunction with increased age.

IL-10 is linked to the is_associated_with::myokines, as exercise provokes an increase in circulating levels of IL-1ra, IL-10, and sTNF-R, suggesting that is_associated_with::physical exercise fosters an environment of anti-inflammatory cytokines.

Lower levels of IL-10 have been observed in individuals diagnosed with is_associated_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. TNFα itself induces demyelination of the oliodendroglial via TNF receptor 1, while chronic inflammation has been linked to demyelination of neurons.

In is_associated_with::melanoma cell lines, IL-10 modules the surface expression of is_associated_with::NKG2D ligands.

Interactions
IL-10 has been shown to interact with is_associated_with::Interleukin 10 receptor, alpha subunit.

The receptor complex for IL-10 also requires the IL10R2 chain to initiate signalling. This ligand–receptor combination is found in birds and frogs, and is also likely to exist in bony fish.