Wikipedia

Interleukin 10

Interleukin 10(IL-10), also known ashuman cytokine synthesis inhibitory factor(CSIF), is an anti-inflammatorycytokine.In humans, interleukin 10 is encoded by theIL10gene.[5]IL-10 signals through a receptor complex consisting of twoIL-10 receptor-1and twoIL-10 receptor-2proteins.[6]Consequently, the functional receptor consists of four IL-10 receptor molecules. IL-10 binding inducesSTAT3 signallingvia thephosphorylationof the cytoplasmic tails of IL-10 receptor 1 + IL-10 receptor 2 byJAK1and Tyk2 respectively.[6]

IL10
Available structures
PDBOrtholog search:PDBeRCSB
Identifiers
AliasesIL10,CSIF, GVHDS, IL-10, IL10A, TGIF, interleukin 10
External IDsOMIM:124092;MGI:96537;HomoloGene:478;GeneCards:IL10;OMA:IL10 - orthologs
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 MbChr 1: 130.95 – 130.95 Mb
PubMedsearch[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Gene and protein structure

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The IL-10 protein is ahomodimer;each of its subunits is 178-amino-acidlong.[7]

IL-10 is classified as a class-2 cytokine, a set of cytokines includingIL-19,IL-20,IL-22,IL-24(Mda-7),IL-26andinterferons type-I(IFN- Alpha,-beta, -epsilon, -kappa, - Omega ),type-II(IFN-gamma) andtype-III(IFN-lambda,[8]includingIL-28A,IL-28B,IL-29,andIFNL4).[9]

Expression and synthesis

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In humans, IL-10 is encoded by theIL10gene, which is located onchromosome 1and comprises fiveexons,[5]and is primarily produced bymonocytesand, to a lesser extent,lymphocytes,namely type-IIT helper cells(TH2),mast cells,CD4+CD25+Foxp3+regulatory T cells,and in a certain subset of activatedT cellsandB cells.IL-10 can be produced by monocytes uponPD-1triggering in these cells.[10]IL-10 upregulation is also mediated byGPCRs,such asbeta-2 adrenergic[11]andtype 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 ofTLRorFc receptorpathways.[14]IL-10 induction involvesERK1/2,p38and NF-κB signalling and transcriptional activation via promoter binding of the transcription factors NF-κB andAP-1.[14]IL-10 may autoregulate its expression via a negative feed-back loop involvingautocrinestimulation 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 ofmRNA stabilityviaAU-rich elements[16]and bymicroRNAssuch aslet-7[17]or miR-106.[18]

Function

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IL-10 is a cytokine with multiple,pleiotropic,effects in immunoregulation and inflammation. It downregulates the expression ofTh1cytokines,MHC class IIantigens, and co-stimulatory molecules onmacrophages.It also enhances B cell survival, proliferation, and antibody production. IL-10 can blockNF-κBactivity, and is involved in the regulation of theJAK-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 fromToll-Like Receptor(TLR) triggeredmyeloid lineage cells.

Effect on tumors

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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

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

IL-10 is capable of inhibiting synthesis of pro-inflammatory cytokines such asIFN-γ,IL-2,IL-3,TNFαandGM-CSFmade by cells such asmacrophagesand 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 themyokines,as exercise provokes an increase in circulating levels of IL-1ra, IL-10, and sTNF-R, suggesting thatphysical exercisefosters an environment of anti-inflammatory cytokines.[38][39]

Lower levels of IL-10 have been observed in individuals diagnosed withmultiple sclerosiswhen compared to healthy individuals.[40]Due to a decrease in IL-10 levels,TNFαlevels 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]

Inmelanomacell lines, IL-10 modulates the surface expression ofNKG2Dligands.[43]

In addition, Forkhead box protein 3 (Foxp3) as a transcription factor is an essential molecular marker of regulatory T (Treg) cells.Foxp3polymorphism (rs3761548) might be involved in cancer progression likegastric cancerthrough influencing Tregs function and the secretion of immunomodulatory cytokines such as IL-10,IL-35,andTGF-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

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Knockoutstudies in mice suggested the function of this cytokine as an essential immunoregulator in the intestinal tract.[47]and, indeed, patients withCrohn's diseasereact favorably towards treatment with recombinant interleukin-10-producing bacteria, demonstrating the importance of IL-10 for counteracting thehyperactive immune responsein 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

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Further to these data, a Phase I immunoncology clinical trial is currently being conducted to assess the therapeutic capacity ofPEGylatedrecombinant 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 generatedin vitroandin 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 2018AM0010 (akapegilodecakin) is in phase 3 clinical trials.[58]

Interactions

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IL-10 has been shown tointeractwithInterleukin 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]

References

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