Interleukin 10

The IL-10 protein is a homodimer; each of its subunits is 178-amino-acid long.{{cite journal | vauthors = Zdanov A, Schalk-Hihi C, Gustchina A, Tsang M, Weatherbee J, Wlodawer A | title = Crystal structure of interleukin-10 reveals the functional dimer with an unexpected topological similarity to interferon gamma | journal = Structure | volume = 3 | issue = 6 | pages = 591–601 | date = June 1995 | pmid = 8590020 | doi = 10.1016/S0969-2126(01)00193-9 | doi-access = free }}

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,{{cite journal | vauthors = Lazear HM, Nice TJ, Diamond MS | title = Interferon-λ: Immune Functions at Barrier Surfaces and Beyond | journal = Immunity | volume = 43 | issue = 1 | pages = 15–28 | date = July 2015 | pmid = 26200010 | pmc = 4527169 | doi = 10.1016/j.immuni.2015.07.001 }} including IL-28A, IL-28B, IL-29, and IFNL4).{{cite journal | vauthors = Pestka S, Krause CD, Sarkar D, Walter MR, Shi Y, Fisher PB | title = Interleukin-10 and related cytokines and receptors | journal = Annual Review of Immunology | volume = 22 | issue = 1 | pages = 929–979 | year = 2004 | pmid = 15032600 | doi = 10.1146/annurev.immunol.22.012703.104622 }}

In humans, IL-10 is encoded by the IL10 gene, which is located on chromosome 1 and comprises five exons, and is primarily produced by monocytes and, to a lesser extent, lymphocytes, namely type-II T helper cells (T_H2), 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.{{cite journal | vauthors = Said EA, Dupuy FP, Trautmann L, Zhang Y, Shi Y, El-Far M, Hill BJ, Noto A, Ancuta P, Peretz Y, Fonseca SG, Van Grevenynghe J, Boulassel MR, Bruneau J, Shoukry NH, Routy JP, Douek DC, Haddad EK, Sekaly RP | title = Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection | journal = Nature Medicine | volume = 16 | issue = 4 | pages = 452–459 | date = April 2010 | pmid = 20208540 | pmc = 4229134 | doi = 10.1038/nm.2106 }} IL-10 upregulation is also mediated by GPCRs, such as beta-2 adrenergic{{cite journal | vauthors = Ağaç D, Estrada LD, Maples R, Hooper LV, Farrar JD | title = The β2-adrenergic receptor controls inflammation by driving rapid IL-10 secretion | journal = Brain, Behavior, and Immunity | volume = 74 | pages = 176–185 | date = November 2018 | pmid = 30195028 | pmc = 6289674 | doi = 10.1016/j.bbi.2018.09.004 }} and type 2 cannabinoid{{cite journal | vauthors = Saroz Y, Kho DT, Glass M, Graham ES, Grimsey NL | title = Cannabinoid Receptor 2 (CB₂) Signals via G-alpha-s and Induces IL-6 and IL-10 Cytokine Secretion in Human Primary Leukocytes | journal = ACS Pharmacology & Translational Science | volume = 2 | issue = 6 | pages = 414–428 | date = December 2019 | pmid = 32259074 | pmc = 7088898 | doi = 10.1021/acsptsci.9b00049 | doi-access = free }} receptors. The expression of IL-10 is minimal in unstimulated tissues and seems to require triggering by commensal or pathogenic flora.{{cite journal | vauthors = Li X, Mai J, Virtue A, Yin Y, Gong R, Sha X, Gutchigian S, Frisch A, Hodge I, Jiang X, Wang H, Yang XF | title = IL-35 is a novel responsive anti-inflammatory cytokine--a new system of categorizing anti-inflammatory cytokines | journal = PLOS ONE | volume = 7 | issue = 3 | pages = e33628 | date = March 2012 | pmid = 22438968 | pmc = 3306427 | doi = 10.1371/journal.pone.0033628 | doi-access = free | bibcode = 2012PLoSO...733628L }} 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.{{cite journal | vauthors = Saraiva M, O'Garra A | title = The regulation of IL-10 production by immune cells | journal = Nature Reviews. Immunology | volume = 10 | issue = 3 | pages = 170–181 | date = March 2010 | pmid = 20154735 | doi = 10.1038/nri2711 | hdl-access = free | s2cid = 6150977 | hdl = 1822/29592 }} 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.{{cite journal | vauthors = Hammer M, Mages J, Dietrich H, Schmitz F, Striebel F, Murray PJ, Wagner H, Lang R | title = Control of dual-specificity phosphatase-1 expression in activated macrophages by IL-10 | journal = European Journal of Immunology | volume = 35 | issue = 10 | pages = 2991–3001 | date = October 2005 | pmid = 16184516 | doi = 10.1002/eji.200526192 | doi-access = free }} Additionally, IL-10 expression is extensively regulated at the post-transcriptional level, which may involve control of mRNA stability via AU-rich elements{{cite journal | vauthors = Powell MJ, Thompson SA, Tone Y, Waldmann H, Tone M | title = Posttranscriptional regulation of IL-10 gene expression through sequences in the 3'-untranslated region | journal = Journal of Immunology | volume = 165 | issue = 1 | pages = 292–296 | date = July 2000 | pmid = 10861064 | doi = 10.4049/jimmunol.165.1.292 | doi-access = free }} and by microRNAs such as let-7{{cite journal | vauthors = Schulte LN, Eulalio A, Mollenkopf HJ, Reinhardt R, Vogel J | title = Analysis of the host microRNA response to Salmonella uncovers the control of major cytokines by the let-7 family | journal = The EMBO Journal | volume = 30 | issue = 10 | pages = 1977–1989 | date = May 2011 | pmid = 21468030 | pmc = 3098495 | doi = 10.1038/emboj.2011.94 }} or miR-106.{{cite journal | vauthors = Sharma A, Kumar M, Aich J, Hariharan M, Brahmachari SK, Agrawal A, Ghosh B | title = Posttranscriptional regulation of interleukin-10 expression by hsa-miR-106a | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 14 | pages = 5761–5766 | date = April 2009 | pmid = 19307576 | pmc = 2659714 | doi = 10.1073/pnas.0808743106 | doi-access = free | bibcode = 2009PNAS..106.5761S }}

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,{{cite journal | vauthors = Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A | title = Interleukin-10 and the interleukin-10 receptor | journal = Annual Review of Immunology | volume = 19 | issue = 1 | pages = 683–765 | date = 2001-01-01 | pmid = 11244051 | doi = 10.1146/annurev.immunol.19.1.683 }} IL-10 was initially reported to suppress cytokine secretion, antigen presentation and CD4+ T cell activation.{{cite journal | vauthors = de Waal Malefyt R, Abrams J, Bennett B, Figdor CG, de Vries JE | title = Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes | journal = The Journal of Experimental Medicine | volume = 174 | issue = 5 | pages = 1209–1220 | date = November 1991 | pmid = 1940799 | pmc = 2119001 | doi = 10.1084/jem.174.5.1209 }}{{cite journal | vauthors = de Waal Malefyt R, Haanen J, Spits H, Roncarolo MG, te Velde A, Figdor C, Johnson K, Kastelein R, Yssel H, de Vries JE | title = Interleukin 10 (IL-10) and viral IL-10 strongly reduce antigen-specific human T cell proliferation by diminishing the antigen-presenting capacity of monocytes via downregulation of class II major histocompatibility complex expression | journal = The Journal of Experimental Medicine | volume = 174 | issue = 4 | pages = 915–924 | date = October 1991 | pmid = 1655948 | pmc = 2118975 | doi = 10.1084/jem.174.4.915 }}{{cite journal | vauthors = Akdis CA, Joss A, Akdis M, Faith A, Blaser K | title = A molecular basis for T cell suppression by IL-10: CD28-associated IL-10 receptor inhibits CD28 tyrosine phosphorylation and phosphatidylinositol 3-kinase binding | journal = FASEB Journal | volume = 14 | issue = 12 | pages = 1666–1668 | date = September 2000 | pmid = 10973911 | doi = 10.1096/fj.99-0874fje | s2cid = 40794643 | doi-access = free }}{{cite journal | vauthors = Joss A, Akdis M, Faith A, Blaser K, Akdis CA | title = IL-10 directly acts on T cells by specifically altering the CD28 co-stimulation pathway | journal = European Journal of Immunology | volume = 30 | issue = 6 | pages = 1683–1690 | date = June 2000 | pmid = 10898505 | doi = 10.1002/1521-4141(200006)30:6<1683::AID-IMMU1683>3.0.CO;2-A | doi-access = free }} Further investigation has shown that IL-10 predominantly inhibits lipopolysaccharide (LPS) and bacterial product mediated induction of the pro-inflammatory cytokines TNFα,{{cite journal | vauthors = Opp MR, Smith EM, Hughes TK | title = Interleukin-10 (cytokine synthesis inhibitory factor) acts in the central nervous system of rats to reduce sleep | journal = Journal of Neuroimmunology | volume = 60 | issue = 1–2 | pages = 165–168 | date = July 1995 | pmid = 7642744 | doi = 10.1016/0165-5728(95)00066-b | s2cid = 3786577 }} IL-1β, IL-12,{{cite journal | vauthors = Aste-Amezaga M, Ma X, Sartori A, Trinchieri G | title = Molecular mechanisms of the induction of IL-12 and its inhibition by IL-10 | journal = Journal of Immunology | volume = 160 | issue = 12 | pages = 5936–5944 | date = June 1998 | pmid = 9637507 | doi = 10.4049/jimmunol.160.12.5936 | s2cid = 15960096 }} and IFNγ{{cite journal | vauthors = Varma TK, Toliver-Kinsky TE, Lin CY, Koutrouvelis AP, Nichols JE, Sherwood ER | title = Cellular mechanisms that cause suppressed gamma interferon secretion in endotoxin-tolerant mice | journal = Infection and Immunity | volume = 69 | issue = 9 | pages = 5249–5263 | date = September 2001 | pmid = 11500393 | pmc = 98633 | doi = 10.1128/iai.69.9.5249-5263.2001 }} secretion from toll-like receptor (TLR) triggered myeloid lineage cells.

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.{{cite journal | vauthors = Zheng LM, Ojcius DM, Garaud F, Roth C, Maxwell E, Li Z, Rong H, Chen J, Wang XY, Catino JJ, King I | title = Interleukin-10 inhibits tumor metastasis through an NK cell-dependent mechanism | journal = The Journal of Experimental Medicine | volume = 184 | issue = 2 | pages = 579–584 | date = August 1996 | pmid = 8760811 | pmc = 2192723 | doi = 10.1084/jem.184.2.579 }} 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{{cite journal | vauthors = Sun H, Jackson MJ, Kundu N, Fulton AM | title = Interleukin-10 gene transfer activates interferon-gamma and the interferon-gamma-inducible genes Gbp-1/Mag-1 and Mig-1 in mammary tumors | journal = International Journal of Cancer | volume = 80 | issue = 4 | pages = 624–629 | date = February 1999 | pmid = 9935167 | doi = 10.1002/(sici)1097-0215(19990209)80:4<624::aid-ijc23>3.0.co;2-9 | doi-access = free }}{{cite journal | vauthors = Sun H, Gutierrez P, Jackson MJ, Kundu N, Fulton AM | title = Essential role of nitric oxide and interferon-gamma for tumor immunotherapy with interleukin-10 | journal = Journal of Immunotherapy | volume = 23 | issue = 2 | pages = 208–214 | date = 2000-04-01 | pmid = 10746547 | doi = 10.1097/00002371-200003000-00005 | s2cid = 39224241 }} in IL-10 transgenic mice{{cite journal | vauthors = Groux H, Cottrez F, Rouleau M, Mauze S, Antonenko S, Hurst S, McNeil T, Bigler M, Roncarolo MG, Coffman RL | title = A transgenic model to analyze the immunoregulatory role of IL-10 secreted by antigen-presenting cells | journal = Journal of Immunology | volume = 162 | issue = 3 | pages = 1723–1729 | date = February 1999 | pmid = 9973435 | doi = 10.4049/jimmunol.162.3.1723 | s2cid = 36990295 | doi-access = free }} or dosing with IL-10 leads to control of primary tumor growth and decreased metastatic burden.{{cite journal | vauthors = Fujii S, Shimizu K, Shimizu T, Lotze MT | title = Interleukin-10 promotes the maintenance of antitumor CD8(+) T-cell effector function in situ | journal = Blood | volume = 98 | issue = 7 | pages = 2143–2151 | date = October 2001 | pmid = 11568001 | doi = 10.1182/blood.v98.7.2143 | doi-access = free }}{{cite journal | vauthors = Berman RM, Suzuki T, Tahara H, Robbins PD, Narula SK, Lotze MT | title = Systemic administration of cellular IL-10 induces an effective, specific, and long-lived immune response against established tumors in mice | journal = Journal of Immunology | volume = 157 | issue = 1 | pages = 231–238 | date = July 1996 | pmid = 8683120 | doi = 10.4049/jimmunol.157.1.231 | s2cid = 25596108 }} More recently, PEGylated recombinant murine IL-10 (PEG-rMuIL-10) has been shown to induce IFNγ and CD8+ T cell dependent anti-tumor immunity.{{cite journal | vauthors = Emmerich J, Mumm JB, Chan IH, LaFace D, Truong H, McClanahan T, Gorman DM, Oft M | title = IL-10 directly activates and expands tumor-resident CD8(+) T cells without de novo infiltration from secondary lymphoid organs | journal = Cancer Research | volume = 72 | issue = 14 | pages = 3570–3581 | date = July 2012 | pmid = 22581824 | doi = 10.1158/0008-5472.CAN-12-0721 | doi-access = free }}{{cite journal | vauthors = Mumm JB, Emmerich J, Zhang X, Chan I, Wu L, Mauze S, Blaisdell S, Basham B, Dai J, Grein J, Sheppard C, Hong K, Cutler C, Turner S, LaFace D, Kleinschek M, Judo M, Ayanoglu G, Langowski J, Gu D, Paporello B, Murphy E, Sriram V, Naravula S, Desai B, Medicherla S, Seghezzi W, McClanahan T, Cannon-Carlson S, Beebe AM, Oft M | title = IL-10 elicits IFNγ-dependent tumor immune surveillance | journal = Cancer Cell | volume = 20 | issue = 6 | pages = 781–796 | date = December 2011 | pmid = 22172723 | doi = 10.1016/j.ccr.2011.11.003 | doi-access = free }} 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.{{cite journal | vauthors = Chan IH, Wu V, Bilardello M, Mar E, Oft M, Van Vlasselaer P, Mumm JB | title = The Potentiation of IFN-γ and Induction of Cytotoxic Proteins by Pegylated IL-10 in Human CD8 T Cells | journal = Journal of Interferon & Cytokine Research | volume = 35 | issue = 12 | pages = 948–955 | date = December 2015 | pmid = 26309093 | doi = 10.1089/jir.2014.0221 }}

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.{{cite journal | vauthors = Grimbaldeston MA, Nakae S, Kalesnikoff J, Tsai M, Galli SJ | title = Mast cell-derived interleukin 10 limits skin pathology in contact dermatitis and chronic irradiation with ultraviolet B | journal = Nature Immunology | volume = 8 | issue = 10 | pages = 1095–1104 | date = October 2007 | pmid = 17767162 | doi = 10.1038/ni1503 | s2cid = 10972672 }}

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.{{cite journal | vauthors = Sikka G, Miller KL, Steppan J, Pandey D, Jung SM, Fraser CD, Ellis C, Ross D, Vandegaer K, Bedja D, Gabrielson K, Walston JD, Berkowitz DE, Barouch LA | title = Interleukin 10 knockout frail mice develop cardiac and vascular dysfunction with increased age | journal = Experimental Gerontology | volume = 48 | issue = 2 | pages = 128–135 | date = February 2013 | pmid = 23159957 | pmc = 3744178 | doi = 10.1016/j.exger.2012.11.001 }}

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.{{cite journal | vauthors = Ostrowski K, Schjerling P, Pedersen BK | title = Physical activity and plasma interleukin-6 in humans--effect of intensity of exercise | journal = European Journal of Applied Physiology | volume = 83 | issue = 6 | pages = 512–515 | date = December 2000 | pmid = 11192058 | doi = 10.1007/s004210000312 | s2cid = 44759539 }}{{cite journal | vauthors = Ostrowski K, Rohde T, Asp S, Schjerling P, Pedersen BK | title = Pro- and anti-inflammatory cytokine balance in strenuous exercise in humans | journal = The Journal of Physiology | volume = 515 | issue = Pt 1 | pages = 287–291 | date = February 1999 | pmid = 9925898 | pmc = 2269132 | doi = 10.1111/j.1469-7793.1999.287ad.x }}

Lower levels of IL-10 have been observed in individuals diagnosed with multiple sclerosis when compared to healthy individuals.{{cite journal | vauthors = Ozenci V, Kouwenhoven M, Huang YM, Xiao B, Kivisäkk P, Fredrikson S, Link H | title = Multiple sclerosis: levels of interleukin-10-secreting blood mononuclear cells are low in untreated patients but augmented during interferon-beta-1b treatment | journal = Scandinavian Journal of Immunology | volume = 49 | issue = 5 | pages = 554–561 | date = May 1999 | pmid = 10320650 | doi = 10.1046/j.1365-3083.1999.00546.x | doi-access = free }} Due to a decrease in IL-10 levels, TNFα levels are not regulated effectively as IL-10 regulates the TNF-α-converting enzyme.{{cite journal | vauthors = Brennan FM, Green P, Amjadi P, Robertshaw HJ, Alvarez-Iglesias M, Takata M | title = Interleukin-10 regulates TNF-alpha-converting enzyme (TACE/ADAM-17) involving a TIMP-3 dependent and independent mechanism | journal = European Journal of Immunology | volume = 38 | issue = 4 | pages = 1106–1117 | date = April 2008 | pmid = 18383040 | doi = 10.1002/eji.200737821 | doi-access = free }} As a result, TNFα levels rise and result in inflammation.{{cite journal | vauthors = Nakahara J, Maeda M, Aiso S, Suzuki N | title = Current concepts in multiple sclerosis: autoimmunity versus oligodendrogliopathy | journal = Clinical Reviews in Allergy & Immunology | volume = 42 | issue = 1 | pages = 26–34 | date = February 2012 | pmid = 22189514 | doi = 10.1007/s12016-011-8287-6 | s2cid = 21058811 }} TNFα itself induces demyelination of the oligodendroglial via TNF receptor 1, while chronic inflammation has been linked to demyelination of neurons.

In melanoma cell lines, IL-10 modulates the surface expression of NKG2D ligands.{{cite journal | vauthors = Serrano AE, Menares-Castillo E, Garrido-Tapia M, Ribeiro CH, Hernández CJ, Mendoza-Naranjo A, Gatica-Andrades M, Valenzuela-Diaz R, Zúñiga R, López MN, Salazar-Onfray F, Aguillón JC, Molina MC | title = Interleukin 10 decreases MICA expression on melanoma cell surface | journal = Immunology and Cell Biology | volume = 89 | issue = 3 | pages = 447–457 | date = March 2011 | pmid = 20714339 | doi = 10.1038/icb.2010.100 | hdl-access = free | s2cid = 205150174 | hdl = 10533/132162 }}

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.{{cite journal | vauthors = Ezzeddini R, Somi MH, Taghikhani M, Moaddab SY, Masnadi Shirazi K, Shirmohammadi M, Eftekharsadat AT, Sadighi Moghaddam B, Salek Farrokhi A | title = Association of Foxp3 rs3761548 polymorphism with cytokines concentration in gastric adenocarcinoma patients | journal = Cytokine | volume = 138 | issue = | pages = 155351 | date = February 2021 | pmid = 33127257 | doi = 10.1016/j.cyto.2020.155351 | s2cid = 226218796 }}

A recent mouse study indicates that IL-10 regulates CD36, a key phagocytosis effector, promoting hematoma clearance after intracerebral hemorrhage.{{cite journal | vauthors = Li Q, Lan X, Han X, Durham F, Wan J, Weiland A, Koehler RC, Wang J | title = Microglia-derived interleukin-10 accelerates post-intracerebral hemorrhage hematoma clearance by regulating CD36 | journal = Brain, Behavior, and Immunity | volume = 94 | pages = 437–457 | date = May 2021 | pmid = 33588074 | pmc = 8058329 | doi = 10.1016/j.bbi.2021.02.001 }} IL-10 deficiency aggravates traumatic brain injury in male but not female mice.{{cite journal | vauthors = Gu Y, Dong Y, Wan J, Ren H, Koehler RC, Wang J | title = Interleukin-10 deficiency aggravates traumatic brain injury in male but not female mice | journal = Experimental Neurology | volume = 355 | pages = 114125 | date = September 2022 | pmid = 35644427 | doi = 10.1016/j.expneurol.2022.114125 | s2cid = 249070122 }}

Knockout studies in mice suggested the function of this cytokine as an essential immunoregulator in the intestinal tract.{{cite web | title = Entrez Gene: IL10 interleukin 10| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3586}} 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.{{cite journal | vauthors = Braat H, Rottiers P, Hommes DW, Huyghebaert N, Remaut E, Remon JP, van Deventer SJ, Neirynck S, Peppelenbosch MP, Steidler L | title = A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn's disease | journal = Clinical Gastroenterology and Hepatology | volume = 4 | issue = 6 | pages = 754–759 | date = June 2006 | pmid = 16716759 | doi = 10.1016/j.cgh.2006.03.028 }}

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{{cite journal | vauthors = Fedorak RN, Gangl A, Elson CO, Rutgeerts P, Schreiber S, Wild G, Hanauer SB, Kilian A, Cohard M, LeBeaut A, Feagan B | title = Recombinant human interleukin 10 in the treatment of patients with mild to moderately active Crohn's disease. The Interleukin 10 Inflammatory Bowel Disease Cooperative Study Group | journal = Gastroenterology | volume = 119 | issue = 6 | pages = 1473–1482 | date = December 2000 | pmid = 11113068 | doi = 10.1053/gast.2000.20229 }}{{cite journal | vauthors = Schreiber S, Fedorak RN, Nielsen OH, Wild G, Williams CN, Nikolaus S, Jacyna M, Lashner BA, Gangl A, Rutgeerts P, Isaacs K, van Deventer SJ, Koningsberger JC, Cohard M, LeBeaut A, Hanauer SB | title = Safety and efficacy of recombinant human interleukin 10 in chronic active Crohn's disease. Crohn's Disease IL-10 Cooperative Study Group | journal = Gastroenterology | volume = 119 | issue = 6 | pages = 1461–1472 | date = December 2000 | pmid = 11113067 | doi = 10.1053/gast.2000.20196 }}{{cite journal | vauthors = van Deventer SJ, Elson CO, Fedorak RN | title = Multiple doses of intravenous interleukin 10 in steroid-refractory Crohn's disease. Crohn's Disease Study Group | journal = Gastroenterology | volume = 113 | issue = 2 | pages = 383–389 | date = August 1997 | pmid = 9247454 | doi = 10.1053/gast.1997.v113.pm9247454 | url = http://dare.uva.nl/personal/pure/en/publications/multiple-doses-of-intravenous-interleukin-10-in-steroidrefractory-crohns-disease(60d5697e-722e-45d0-bb16-8fcca122c5f4).html }} or rheumatoid arthritis.{{cite journal | vauthors = van Roon J, Wijngaarden S, Lafeber FP, Damen C, van de Winkel J, Bijlsma JW | title = Interleukin 10 treatment of patients with rheumatoid arthritis enhances Fc gamma receptor expression on monocytes and responsiveness to immune complex stimulation | journal = The Journal of Rheumatology | volume = 30 | issue = 4 | pages = 648–651 | date = April 2003 | pmid = 12672180 }} rHuIL-10 treatment initially exhibited promising clinical data in psoriasis,{{cite journal | vauthors = Asadullah K, Döcke WD, Ebeling M, Friedrich M, Belbe G, Audring H, Volk HD, Sterry W | title = Interleukin 10 treatment of psoriasis: clinical results of a phase 2 trial | journal = Archives of Dermatology | volume = 135 | issue = 2 | pages = 187–192 | date = February 1999 | pmid = 10052405 | doi = 10.1001/archderm.135.2.187 }} but failed to achieve clinical significance in a randomized, double blind, placebo controlled Phase II trial.{{cite journal | vauthors = Kimball AB, Kawamura T, Tejura K, Boss C, Hancox AR, Vogel JC, Steinberg SM, Turner ML, Blauvelt A | title = Clinical and immunologic assessment of patients with psoriasis in a randomized, double-blind, placebo-controlled trial using recombinant human interleukin 10 | journal = Archives of Dermatology | volume = 138 | issue = 10 | pages = 1341–1346 | date = October 2002 | pmid = 12374540 | doi = 10.1001/archderm.138.10.1341 | doi-access = free }} Further investigation of rHuIL-10's effects in humans suggests that rather than inhibiting inflammation, rHuIL-10 is capable of exerting pro-inflammatory effects.{{cite journal | vauthors = Lauw FN, Pajkrt D, Hack CE, Kurimoto M, van Deventer SJ, van der Poll T | title = Proinflammatory effects of IL-10 during human endotoxemia | journal = Journal of Immunology | volume = 165 | issue = 5 | pages = 2783–2789 | date = September 2000 | pmid = 10946310 | doi = 10.4049/jimmunol.165.5.2783 | doi-access = free }}{{cite journal | vauthors = Tilg H, van Montfrans C, van den Ende A, Kaser A, van Deventer SJ, Schreiber S, Gregor M, Ludwiczek O, Rutgeerts P, Gasche C, Koningsberger JC, Abreu L, Kuhn I, Cohard M, LeBeaut A, Grint P, Weiss G | title = Treatment of Crohn's disease with recombinant human interleukin 10 induces the proinflammatory cytokine interferon gamma | journal = Gut | volume = 50 | issue = 2 | pages = 191–195 | date = February 2002 | pmid = 11788558 | pmc = 1773093 | doi = 10.1136/gut.50.2.191 }}

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).{{cite journal | vauthors = Infante JR, Naing A, Papadopoulos KP, Autio KA, Ott PA, Wong DJ, Falchook GS, Patel MR, Pant S, Whiteside M, Bendell JC |title = A first-in-human dose escalation study of PEGylated recombinant human IL-10 (AM0010) in advanced solid tumors.|url = http://hwmaint.meeting.ascopubs.org/cgi/content/abstract/33/15_suppl/3017|journal = ASCO Meeting Abstracts|date = 2015-05-20|pages = 3017|volume = 33|issue = 15_suppl |access-date = 2015-12-10|archive-date = 2015-12-22|archive-url = https://web.archive.org/web/20151222154311/http://hwmaint.meeting.ascopubs.org/cgi/content/abstract/33/15_suppl/3017 |url-status = dead}} Consistent with preclinical immunoncology data, investigators report substantial anti-tumor efficacy. Contrary to the reported immunosuppressive effects of IL-10 generated in vitro and in vivo, 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. 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. These findings are consistent with the published preclinical immunoncology reports using PEG-rMuIL-10 and with previous findings treating humans with rHuIL-10. 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.[https://immuno-oncologynews.com/2018/04/02/early-data-supports-armos-pegilodecakin-phase-3-trial-in-metastatic-pancreatic-cancer-patients/ Early Data Supports Phase 3 Trial of Pegilodecakin as Possible Treatment for Advanced Pancreatic Cancer]

IL-10 has been shown to interact with Interleukin 10 receptor, alpha subunit.{{cite journal | vauthors = Ho AS, Liu Y, Khan TA, Hsu DH, Bazan JF, Moore KW | title = A receptor for interleukin 10 is related to interferon receptors | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 23 | pages = 11267–11271 | date = December 1993 | pmid = 8248239 | pmc = 47963 | doi = 10.1073/pnas.90.23.11267 | doi-access = free | bibcode = 1993PNAS...9011267H }}{{cite journal | vauthors = Josephson K, Logsdon NJ, Walter MR | title = Crystal structure of the IL-10/IL-10R1 complex reveals a shared receptor binding site | journal = Immunity | volume = 15 | issue = 1 | pages = 35–46 | date = July 2001 | pmid = 11485736 | doi = 10.1016/S1074-7613(01)00169-8 | doi-access = free }}{{cite journal | vauthors = Tan JC, Braun S, Rong H, DiGiacomo R, Dolphin E, Baldwin S, Narula SK, Zavodny PJ, Chou CC | title = Characterization of recombinant extracellular domain of human interleukin-10 receptor | journal = The Journal of Biological Chemistry | volume = 270 | issue = 21 | pages = 12906–12911 | date = May 1995 | pmid = 7759550 | doi = 10.1074/jbc.270.21.12906 | doi-access = free }}{{cite journal | vauthors = Josephson K, McPherson DT, Walter MR | title = Purification, crystallization and preliminary X-ray diffraction of a complex between IL-10 and soluble IL-10R1 | journal = Acta Crystallographica. Section D, Biological Crystallography | volume = 57 | issue = Pt 12 | pages = 1908–1911 | date = December 2001 | pmid = 11717514 | doi = 10.1107/S0907444901016249 | bibcode = 2001AcCrD..57.1908J }}{{cite journal | vauthors = Hoover DM, Schalk-Hihi C, Chou CC, Menon S, Wlodawer A, Zdanov A | title = Purification of receptor complexes of interleukin-10 stoichiometry and the importance of deglycosylation in their crystallization | journal = European Journal of Biochemistry | volume = 262 | issue = 1 | pages = 134–141 | date = May 1999 | pmid = 10231374 | doi = 10.1046/j.1432-1327.1999.00363.x | doi-access = free }}

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|date=August 2012}}

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{{refend}}

• {{Commons category-inline|Interferons or interleukin-10 (IL-10)}}
• {{MeshName|Interleukin-10}}

{{PDB Gallery|geneid=3586}}

{{Interleukins}}

{{Interleukin receptor modulators}}

Category:Interleukins