Interleukin 10

Last updated
IL10
IL10 Crystal Structure.rsh.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases IL10 , CSIF, GVHDS, IL-10, IL10A, TGIF, interleukin 10
External IDs OMIM: 124092 MGI: 96537 HomoloGene: 478 GeneCards: IL10
Orthologs
SpeciesHumanMouse
Entrez

3586

16153

Ensembl

ENSG00000136634

ENSMUSG00000016529

UniProt

P22301

P18893

RefSeq (mRNA)

NM_000572

NM_010548

RefSeq (protein)

NP_000563

NP_034678

Location (UCSC) Chr 1: 206.77 – 206.77 Mb Chr 1: 130.95 – 130.95 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Interleukin 10 (IL-10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory cytokine. In humans, interleukin 10 is encoded by the IL10 gene. [5] IL-10 signals through a receptor complex consisting of two IL-10 receptor-1 and two IL-10 receptor-2 proteins. [6] 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. [6]

Contents

Gene and protein structure

The IL-10 protein is a homodimer; each of its subunits is 178-amino-acid long. [7]

IL-10 is classified as a class-2 cytokine, a set of cytokines including IL-19, IL-20, IL-22, IL-24 (Mda-7), IL-26 and interferons type-I (IFN-alpha, -beta, -epsilon, -kappa, -omega), type-II (IFN-gamma) and type-III (IFN-lambda, [8] including IL-28A, IL-28B, IL-29, and IFNL4). [9]

Expression and synthesis

In humans, IL-10 is encoded by the IL10 gene, which is located on chromosome 1 and comprises 5 exons, [5] and is primarily produced by monocytes and, to a lesser extent, lymphocytes, namely type-II 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 can be produced by monocytes upon PD-1 triggering in these cells. [10] IL-10 upregulation is also mediated by GPCRs, such as beta-2 adrenergic [11] and type 2 cannabinoid [12] receptors. The expression of IL-10 is minimal in unstimulated tissues and seems to require triggering by commensal or pathogenic flora. [13] 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 TLR or Fc receptor pathways. [14] 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. [14] 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. [15] Additionally, IL-10 expression is extensively regulated at the post-transcriptional level, which may involve control of mRNA stability via AU-rich elements [16] and by microRNAs such as let-7 [17] or miR-106. [18]

Function

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, [19] IL-10 was initially reported to suppress cytokine secretion, antigen presentation and CD4+ T cell activation. [20] [21] [22] [23] Further investigation has shown that IL-10 predominantly inhibits lipopolysaccharide (LPS) and bacterial product mediated induction of the pro-inflammatory cytokines TNFα, [24] IL-1β, [24] IL-12, [25] and IFNγ [26] secretion from Toll-Like Receptor (TLR) triggered myeloid lineage cells.

Effect on tumors

Over time a more nuanced picture of IL-10's function has emerged as treatment of tumor bearing mice has been shown to inhibit tumor metastasis. [27] Additional investigation by multiple laboratories has generated data that further supports IL-10's immunostimulatory capacity in an immunoncology context. Expression of IL-10 from transfected tumor cell lines [28] [29] in IL-10 transgenic mice [30] or dosing with IL-10 leads to control of primary tumor growth and decreased metastatic burden. [31] [32] More recently, PEGylated recombinant murine IL-10 (PEG-rMuIL-10) has been shown to induce IFNγ and CD8+ T cell dependent anti-tumor immunity. [33] [34] More specifically, PEGylated recombinant human IL-10 (PEG-rHuIL-10) has been shown to enhance CD8+ T cell secretion of the cytotoxic molecules Granzyme B and Perforin and potentiate T cell receptor dependent IFNγ secretion. [35]

Role in disease

A study in mice has shown that IL-10 is also produced by mast cells, counteracting the inflammatory effect that these cells have at the site of an allergic reaction. [36]

IL-10 is capable of inhibiting synthesis of pro-inflammatory cytokines such as IFN-γ, IL-2, IL-3, TNFα and GM-CSF made by cells such as macrophages and Th1 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. [37]

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. [38] [39]

Lower levels of IL-10 have been observed in individuals diagnosed with multiple sclerosis when compared to healthy individuals. [40] Due to a decrease in IL-10 levels, TNFα levels are not regulated effectively as IL-10 regulates the TNF-α-converting enzyme. [41] As a result, TNFα levels rise and result in inflammation. [42] TNFα itself induces demyelination of the oligodendroglial via TNF receptor 1, while chronic inflammation has been linked to demyelination of neurons. [42]

In melanoma cell lines, IL-10 modulates the surface expression of NKG2D ligands. [43]

In addition, Forkhead box protein 3 (Foxp3) as a transcription factor is an essential molecular marker of regulatory T (Treg) cells. Foxp3 polymorphism (rs3761548) might be involved in cancer progression like gastric cancer through influencing Tregs function and the secretion of immunomodulatory cytokines such as IL-10, IL-35, and TGF-β. [44]

A recent mouse study indicates that IL-10 regulates CD36, a key phagocytosis effector, promoting hematoma clearance after intracerebral hemorrhage. [45] IL-10 deficiency aggravates traumatic brain injury in male but not female mice. [46]

Clinical use or trials

Knockout studies in mice suggested the function of this cytokine as an essential immunoregulator in the intestinal tract. [47] and, indeed, 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. [48]

Due to the data, thousands of patients with a variety of autoimmune diseases were treated with recombinant human IL-10 (rHuIL-10) in clinical trials. Contrary to expectations, rHuIL-10 treatment did not significantly impact disease in patients with Crohn's disease [49] [50] [51] or rheumatoid arthritis. [52] rHuIL-10 treatment initially exhibited promising clinical data in psoriasis, [53] but failed to achieve clinical significance in a randomized, double blind, placebo controlled Phase II trial. [54] Further investigation of rHuIL-10's effects in humans suggests that rather than inhibiting inflammation, rHuIL-10 is capable of exerting pro-inflammatory effects. [55] [56]

PEGylated forms

Further to these data, 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). [57] Consistent with preclinical immunoncology data, investigators report substantial anti-tumor efficacy. [57] Contrary to the reported immunosuppressive effects of IL-10 generated in vitro and in vivo, [21] [22] [23] [24] [25] treatment of cancer patients with PEG-rHuIL-10 elicits a dose titratable induction of the immune stimulatory cytokines IFNγ, IL-18, IL-7, GM-CSF and IL-4. [57] Furthermore, treated patients exhibit fold increases of peripheral CD8+ T cells expressing markers of activation, such as programmed death 1 (PD1)+, lymphocyte activation gene 3 (LAG3)+ and increased Fas Ligand (FasL) and a decrease in serum TGFβ. [57] These findings are consistent with the published preclinical immunoncology reports using PEG-rMuIL-10 [33] [34] and with previous findings treating humans with rHuIL-10. [55] [56] These data suggest that while IL-10 can exert immunosuppressive effects in context of bacterial product stimulated myeloid cells, rHuIL-10/PEG-rHuIL-10 treatment of humans is predominantly immunostimulatory. As of 2018 AM0010 (aka pegilodecakin) is in phase 3 clinical trials. [58]

Interactions

IL-10 has been shown to interact with Interleukin 10 receptor, alpha subunit. [59] [60] [61] [62] [63]

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.[ citation needed ]

Related Research Articles

<span class="mw-page-title-main">Cytokine</span> Broad and loose category of small proteins important in cell signaling

Cytokines are a broad and loose category of small proteins important in cell signaling. Due to their size, cytokines cannot cross the lipid bilayer of cells to enter the cytoplasm and therefore typically exert their functions by interacting with specific cytokine receptors on the target cell surface. Cytokines have been shown to be involved in autocrine, paracrine and endocrine signaling as immunomodulating agents.

<span class="mw-page-title-main">Macrophage</span> Type of white blood cell

Macrophages are a type of white blood cell of the innate immune system that engulf and digest pathogens, such as cancer cells, microbes, cellular debris, and foreign substances, which do not have proteins that are specific to healthy body cells on their surface. This process is called phagocytosis, which acts to defend the host against infection and injury.

Interleukins (ILs) are a group of cytokines that are expressed and secreted by white blood cells (leukocytes) as well as some other body cells. The human genome encodes more than 50 interleukins and related proteins.

<span class="mw-page-title-main">Interleukin 12</span> Interleukin

Interleukin 12 (IL-12) is an interleukin that is naturally produced by dendritic cells, macrophages, neutrophils, helper T cells and human B-lymphoblastoid cells (NC-37) in response to antigenic stimulation. IL-12 belongs to the family of interleukin-12. IL-12 family is unique in comprising the only heterodimeric cytokines, which includes IL-12, IL-23, IL-27 and IL-35. Despite sharing many structural features and molecular partners, they mediate surprisingly diverse functional effects.

<span class="mw-page-title-main">Interleukin 4</span> Mammalian protein found in Mus musculus

The interleukin 4 is a cytokine that induces differentiation of naive helper T cells (Th0 cells) to Th2 cells. Upon activation by IL-4, Th2 cells subsequently produce additional IL-4 in a positive feedback loop. IL-4 is produced primarily by mast cells, Th2 cells, eosinophils and basophils. It is closely related and has functions similar to IL-13.

<span class="mw-page-title-main">Interferon gamma</span> InterPro Family

Interferon gamma is a dimerized soluble cytokine that is the only member of the type II class of interferons. The existence of this interferon, which early in its history was known as immune interferon, was described by E. F. Wheelock as a product of human leukocytes stimulated with phytohemagglutinin, and by others as a product of antigen-stimulated lymphocytes. It was also shown to be produced in human lymphocytes. or tuberculin-sensitized mouse peritoneal lymphocytes challenged with Mantoux test (PPD); the resulting supernatants were shown to inhibit growth of vesicular stomatitis virus. Those reports also contained the basic observation underlying the now widely employed interferon gamma release assay used to test for tuberculosis. In humans, the IFNG protein is encoded by the IFNG gene.

<span class="mw-page-title-main">Interleukin 23 subunit alpha</span>

Interleukin-23 subunit alpha is a protein that in humans is encoded by the IL23A gene. The protein is also known as IL-23p19. It is one of the two subunits of the cytokine Interleukin-23.

<span class="mw-page-title-main">Interleukin 15</span> Cytokine with structural similarity to Interleukin-2

Interleukin-15 (IL-15) is a protein that in humans is encoded by the IL15 gene. IL-15 is an inflammatory cytokine with structural similarity to Interleukin-2 (IL-2). Like IL-2, IL-15 binds to and signals through a complex composed of IL-2/IL-15 receptor beta chain (CD122) and the common gamma chain. IL-15 is secreted by mononuclear phagocytes following infection by virus(es). This cytokine induces the proliferation of natural killer cells, i.e. cells of the innate immune system whose principal role is to kill virally infected cells.

<span class="mw-page-title-main">Interleukin 21</span> Mammalian protein found in humans

Interleukin 21 (IL-21) is a protein that in humans is encoded by the IL21 gene.

<span class="mw-page-title-main">Interleukin 30</span> Protein-coding gene in the species Homo sapiens

Interleukin 30 (IL-30) forms one chain of the heterodimeric cytokine called interleukin 27 (IL-27), thus it is also called IL27-p28. IL-27 is composed of α chain p28 and β chain Epstain-Barr induce gene-3 (EBI3). The p28 subunit, or IL-30, has an important role as a part of IL-27, but it can be secreted as a separate monomer and has its own functions in the absence of EBI3. The discovery of IL-30 as individual cytokine is relatively new and thus its role in the modulation of the immune response is not fully understood.

<span class="mw-page-title-main">Interleukin 29</span> Protein-coding gene in the species Homo sapiens

Interleukin-29 (IL-29) is a cytokine and it belongs to type III interferons group, also termed interferons λ (IFN-λ). IL-29 plays an important role in the immune response against pathogenes and especially against viruses by mechanisms similar to type I interferons, but targeting primarily cells of epithelial origin and hepatocytes.

<span class="mw-page-title-main">Interleukin 26</span>

Interleukin-26 (IL-26) is a protein that in humans is encoded by the IL26 gene.

<span class="mw-page-title-main">Interleukin 17</span> Group of proteins

Interleukin 17 family is a family of pro-inflammatory cystine knot cytokines. They are produced by a group of T helper cell known as T helper 17 cell in response to their stimulation with IL-23. Originally, Th17 was identified in 1993 by Rouvier et al. who isolated IL17A transcript from a rodent T-cell hybridoma. The protein encoded by IL17A is a founding member of IL-17 family. IL17A protein exhibits a high homology with a viral IL-17-like protein encoded in the genome of T-lymphotropic rhadinovirus Herpesvirus saimiri. In rodents, IL-17A is often referred to as CTLA8.

<span class="mw-page-title-main">Interleukin 19</span> Protein-coding gene in the species Homo sapiens

Interleukin 19 (IL-19) is an immunosuppressive protein that belongs to the IL-10 cytokine subfamily.

<span class="mw-page-title-main">Tyrosine kinase 2</span> Enzyme and coding gene in humans

Non-receptor tyrosine-protein kinase TYK2 is an enzyme that in humans is encoded by the TYK2 gene.

Interleukin 35 (IL-35) is a recently discovered anti-inflammatory cytokine from the IL-12 family. Member of IL-12 family - IL-35 is produced by wide range of regulatory lymphocytes and plays a role in immune suppression. IL-35 can block the development of Th1 and Th17 cells by limiting early T cell proliferation.

Interleukin-28 receptor is a type II cytokine receptor found largely in epithelial cells. It binds type 3 interferons, interleukin-28 A, Interleukin-28B, interleukin 29 and interferon lambda 4. It consists of an α chain and shares a common β subunit with the interleukin-10 receptor. Binding to the interleukin-28 receptor, which is restricted to select cell types, is important for fighting infection. Binding of the type 3 interferons to the receptor results in activation of the JAK/STAT signaling pathway.

<span class="mw-page-title-main">Interleukin-17A</span> Protein-coding gene in the species Homo sapiens

Interleukin-17A is a protein that in humans is encoded by the IL17A gene. In rodents, IL-17A used to be referred to as CTLA8, after the similarity with a viral gene.

<span class="mw-page-title-main">Interleukin-1 family</span> Group of cytokines playing a key role in the regulation of immune and inflammatory responses

The Interleukin-1 family is a group of 11 cytokines that plays a central role in the regulation of immune and inflammatory responses to infections or sterile insults.

The IL-10 family is a family of interleukins.

References

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