| Interleukin 10 |
PDB rendering based on 2H24. |
| Available structures |
| PDB |
Ortholog search: PDBe, RCSB |
| List of PDB id codes |
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1ILK, 1INR, 1J7V, 1LK3, 1Y6K, 2H24, 2ILK
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| Identifiers |
| Symbols |
IL10 ; CSIF; GVHDS; IL-10; IL10A; TGIF |
| External IDs |
OMIM: 124092 MGI: 96537 HomoloGene: 478 GeneCards: IL10 Gene |
| Gene ontology |
| Molecular function |
• cytokine activity
• interleukin-10 receptor binding
• growth factor activity
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| Cellular component |
• extracellular space
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| Biological process |
• response to molecule of bacterial origin
• negative regulation of cytokine secretion involved in immune response
• negative regulation of chronic inflammatory response to antigenic stimulus
• positive regulation of B cell apoptotic process
• inflammatory response
• cytoplasmic sequestering of NF-kappaB
• cell-cell signaling
• regulation of gene expression
• response to activity
• response to inactivity
• hemopoiesis
• B cell differentiation
• leukocyte chemotaxis
• negative regulation of myeloid dendritic cell activation
• negative regulation of B cell proliferation
• negative regulation of interferon-gamma production
• negative regulation of interleukin-12 production
• negative regulation of interleukin-6 production
• negative regulation of tumor necrosis factor production
• receptor biosynthetic process
• response to insulin
• response to carbon monoxide
• type 2 immune response
• B cell proliferation
• negative regulation of T cell proliferation
• response to drug
• negative regulation of tumor necrosis factor biosynthetic process
• defense response to bacterium
• negative regulation of apoptotic process
• negative regulation of growth of symbiont in host
• negative regulation of nitric oxide biosynthetic process
• regulation of isotype switching
• negative regulation of MHC class II biosynthetic process
• positive regulation of MHC class II biosynthetic process
• negative regulation of interferon-alpha biosynthetic process
• positive regulation of transcription, DNA-templated
• positive regulation of transcription from RNA polymerase II promoter
• positive regulation of cytokine secretion
• negative regulation of membrane protein ectodomain proteolysis
• positive regulation of sequence-specific DNA binding transcription factor activity
• response to glucocorticoid
• regulation of sensory perception of pain
• branching involved in labyrinthine layer morphogenesis
• cellular response to lipopolysaccharide
• cellular response to estradiol stimulus
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| Sources: Amigo / QuickGO |
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| RNA expression pattern |
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| More reference expression data |
| Orthologs |
| Species |
Human |
Mouse |
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| Entrez |
3586 |
16153 |
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| Ensembl |
ENSG00000136634 |
ENSMUSG00000016529 |
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| UniProt |
P22301 |
P18893 |
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| RefSeq (mRNA) |
NM_000572 |
NM_010548 |
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| RefSeq (protein) |
NP_000563 |
NP_034678 |
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| Location (UCSC) |
Chr 1:
206.94 – 206.95 Mb |
Chr 1:
131.02 – 131.02 Mb |
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| PubMed search |
[1] |
[2] |
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Interleukin-10 (IL-10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory cytokine. In humans, IL-10 is encoded by the IL10 gene.[1] IL-10 signals through a receptor complex consisting of two IL-10 receptor-1 and two IL-10 receptor 2 proteins.[2] 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.[2]
Contents
- 1 Gene and protein structure
- 2 Expression and synthesis
- 3 Function
- 4 Role in disease
- 5 References
- 6 Further reading
- 7 External links
Gene and protein structure
The IL-10 protein is a homodimer; each of its subunits is 178-amino-acid long.[3]
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).[4]
Expression and synthesis
In humans, IL-10 is encoded by the IL10 gene, which is located on chromosome 1 and comprises 5 exons,[1] and is primarily produced by monocytes and, to a lesser extent, lymphocytes, namely type 2 T helper cells (TH2), mastocytes, 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.[5] The expression of IL-10 is minimal in unstimulated tissues and seems to require triggering by commensal or pathogenic flora.[6] 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.[7] 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.[7] 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.[8] Additionally, IL-10 expression is extensively regulated at the post-transcriptional level, which may involve control of mRNA stability via AU-rich elements[9] and by microRNAs such as let-7[10] or miR-106.[11]
IL-10 is released by cytotoxic T-cells to inhibit the action of NK cells during the immune response to viral infection.[1]
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.
Role in disease
Knockout studies in mice suggested the function of this cytokine as an essential immunoregulator in the intestinal tract.[12] 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.[13]
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.[14]
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 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.[15]
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.[16][17]
Lower levels of IL-10 have been observed in individuals diagnosed with Multiple Sclerosis when compared to healthy individuals.[18] Due to a decrease in IL-10 levels, TNFα levels are not regulated effectively as IL-10 regulates the TNF-α-converting enzyme.[19] As a result, TNFα levels rise and result in inflammation.[20] TNFα itself induces demyelination of the oliodendroglial via TNF receptor 1, while chronic inflammation has been linked to demyelination of neurons.[20]
In melanoma cell lines, IL-10 modules the surface expression of NKG2D ligands.[21]
Interactions
IL-10 has been shown to interact with Interleukin 10 receptor, alpha subunit.[22][23][24][25][26]
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
- ^ a b c Eskdale J, Kube D, Tesch H, Gallagher G (1997). "Mapping of the human IL10 gene and further characterization of the 5' flanking sequence". Immunogenetics 46 (2): 120–8. doi:10.1007/s002510050250. PMID 9162098.
- ^ a b Mosser DM, Zhang X (Dec 2008). "Interleukin-10: new perspectives on an old cytokine". Immunological Reviews 226 (1): 205–18. doi:10.1111/j.1600-065X.2008.00706.x. PMC 2724982. PMID 19161426.
- ^ Zdanov A, Schalk-Hihi C, Gustchina A, Tsang M, Weatherbee J, Wlodawer A (Jun 1995). "Crystal structure of interleukin-10 reveals the functional dimer with an unexpected topological similarity to interferon gamma". Structure 3 (6): 591–601. doi:10.1016/S0969-2126(01)00193-9. PMID 8590020.
- ^ Pestka S, Krause CD, Sarkar D, Walter MR, Shi Y, Fisher PB (2004). "Interleukin-10 and related cytokines and receptors". Annual Review of Immunology 22 (1): 929–79. doi:10.1146/annurev.immunol.22.012703.104622. PMID 15032600.
- ^ Said EA, Dupuy FP, Trautmann L, Zhang Y, Shi Y, El-Far M et al. (Apr 2010). "Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection". Nature Medicine 16 (4): 452–9. doi:10.1038/nm.2106. PMC 4229134. PMID 20208540.
- ^ Li X, Mai J, Virtue A, Yin Y, Gong R, Sha X et al. (March 2012). "IL-35 is a novel responsive anti-inflammatory cytokine--a new system of categorizing anti-inflammatory cytokines". PloS One 7 (3): e33628. doi:10.1371/journal.pone.0033628. PMID 22438968.
- ^ a b Saraiva M, O'Garra A (Mar 2010). "The regulation of IL-10 production by immune cells". Nature Reviews. Immunology 10 (3): 170–81. doi:10.1038/nri2711. PMID 20154735.
- ^ Hammer M, Mages J, Dietrich H, Schmitz F, Striebel F, Murray PJ et al. (Oct 2005). "Control of dual-specificity phosphatase-1 expression in activated macrophages by IL-10". European Journal of Immunology 35 (10): 2991–3001. doi:10.1002/eji.200526192. PMID 16184516.
- ^ Powell MJ, Thompson SA, Tone Y, Waldmann H, Tone M (Jul 2000). "Posttranscriptional regulation of IL-10 gene expression through sequences in the 3'-untranslated region". Journal of Immunology 165 (1): 292–6. doi:10.4049/jimmunol.165.1.292. PMID 10861064.
- ^ Schulte LN, Eulalio A, Mollenkopf HJ, Reinhardt R, Vogel J (May 2011). "Analysis of the host microRNA response to Salmonella uncovers the control of major cytokines by the let-7 family". The EMBO Journal 30 (10): 1977–89. doi:10.1038/emboj.2011.94. PMID 21468030.
- ^ Sharma A, Kumar M, Aich J, Hariharan M, Brahmachari SK, Agrawal A et al. (Apr 2009). "Posttranscriptional regulation of interleukin-10 expression by hsa-miR-106a". Proceedings of the National Academy of Sciences of the United States of America 106 (14): 5761–6. doi:10.1073/pnas.0808743106. PMID 19307576.
- ^ "Entrez Gene: IL10 interleukin 10".
- ^ Braat H, Rottiers P, Hommes DW, Huyghebaert N, Remaut E, Remon JP et al. (Jun 2006). "A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn's disease". Clinical Gastroenterology and Hepatology 4 (6): 754–9. doi:10.1016/j.cgh.2006.03.028. PMID 16716759.
- ^ Grimbaldeston MA, Nakae S, Kalesnikoff J, Tsai M, Galli SJ (Oct 2007). "Mast cell-derived interleukin 10 limits skin pathology in contact dermatitis and chronic irradiation with ultraviolet B". Nature Immunology 8 (10): 1095–104. doi:10.1038/ni1503. PMID 17767162.
- ^ Sikka G, Miller KL, Steppan J, Pandey D, Jung SM, Fraser CD et al. (Feb 2013). "Interleukin 10 knockout frail mice develop cardiac and vascular dysfunction with increased age". Experimental Gerontology 48 (2): 128–35. doi:10.1016/j.exger.2012.11.001. PMC 3744178. PMID 23159957.
- ^ Ostrowski K, Schjerling P, Pedersen BK (Dec 2000). "Physical activity and plasma interleukin-6 in humans--effect of intensity of exercise". European Journal of Applied Physiology 83 (6): 512–5. doi:10.1007/s004210000312. PMID 11192058.
- ^ Ostrowski K, Rohde T, Asp S, Schjerling P, Pedersen BK (Feb 1999). "Pro- and anti-inflammatory cytokine balance in strenuous exercise in humans". The Journal of Physiology. 515 ( Pt 1) (1): 287–91. doi:10.1111/j.1469-7793.1999.287ad.x. PMC 2269132. PMID 9925898.
- ^ Ozenci V, Kouwenhoven M, Huang YM, Xiao B, Kivisäkk P, Fredrikson S et al. (May 1999). "Multiple sclerosis: levels of interleukin-10-secreting blood mononuclear cells are low in untreated patients but augmented during interferon-beta-1b treatment". Scandinavian Journal of Immunology 49 (5): 554–61. doi:10.1046/j.1365-3083.1999.00546.x. PMID 10320650.
- ^ Brennan FM, Green P, Amjadi P, Robertshaw HJ, Alvarez-Iglesias M, Takata M (Apr 2008). "Interleukin-10 regulates TNF-alpha-converting enzyme (TACE/ADAM-17) involving a TIMP-3 dependent and independent mechanism". European Journal of Immunology 38 (4): 1106–17. doi:10.1002/eji.200737821. PMID 18383040.
- ^ a b Nakahara J, Maeda M, Aiso S, Suzuki N (Feb 2012). "Current concepts in multiple sclerosis: autoimmunity versus oligodendrogliopathy". Clinical Reviews in Allergy & Immunology 42 (1): 26–34. doi:10.1007/s12016-011-8287-6. PMID 22189514.
- ^ Serrano AE, Menares-Castillo E, Garrido-Tapia M, Ribeiro CH, Hernández CJ, Mendoza-Naranjo A et al. (Mar 2011). "Interleukin 10 decreases MICA expression on melanoma cell surface". Immunology and Cell Biology 89 (3): 447–57. doi:10.1038/icb.2010.100. PMID 20714339.
- ^ Ho AS, Liu Y, Khan TA, Hsu DH, Bazan JF, Moore KW (Dec 1993). "A receptor for interleukin 10 is related to interferon receptors". Proceedings of the National Academy of Sciences of the United States of America 90 (23): 11267–71. doi:10.1073/pnas.90.23.11267. PMC 47963. PMID 8248239.
- ^ Josephson K, Logsdon NJ, Walter MR (Jul 2001). "Crystal structure of the IL-10/IL-10R1 complex reveals a shared receptor binding site". Immunity 15 (1): 35–46. doi:10.1016/S1074-7613(01)00169-8. PMID 11485736.
- ^ Tan JC, Braun S, Rong H, DiGiacomo R, Dolphin E, Baldwin S et al. (May 1995). "Characterization of recombinant extracellular domain of human interleukin-10 receptor". The Journal of Biological Chemistry 270 (21): 12906–11. doi:10.1074/jbc.270.21.12906. PMID 7759550.
- ^ Josephson K, McPherson DT, Walter MR (Dec 2001). "Purification, crystallization and preliminary X-ray diffraction of a complex between IL-10 and soluble IL-10R1". Acta Crystallographica. Section D, Biological Crystallography 57 (Pt 12): 1908–11. doi:10.1107/S0907444901016249. PMID 11717514.
- ^ Hoover DM, Schalk-Hihi C, Chou CC, Menon S, Wlodawer A, Zdanov A (May 1999). "Purification of receptor complexes of interleukin-10 stoichiometry and the importance of deglycosylation in their crystallization". European Journal of Biochemistry / FEBS 262 (1): 134–41. doi:10.1046/j.1432-1327.1999.00363.x. PMID 10231374.
Further reading
- Bortesi L, Rossato M, Schuster F, Raven N, Stadlmann J, Avesani L et al. (2009). "Viral and murine interleukin-10 are correctly processed and retain their biological activity when produced in tobacco". BMC Biotechnology 9 (1): 22. doi:10.1186/1472-6750-9-22. PMC 2667500. PMID 19298643.
- Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A (2001). "Interleukin-10 and the interleukin-10 receptor". Annual Review of Immunology 19 (1): 683–765. doi:10.1146/annurev.immunol.19.1.683. PMID 11244051.
- Girndt M (2003). "Humoral immune responses in uremia and the role of IL-10". Blood Purification 20 (5): 485–8. doi:10.1159/000063553. PMID 12207099.
- Beebe AM, Cua DJ, de Waal Malefyt R (2003). "The role of interleukin-10 in autoimmune disease: systemic lupus erythematosus (SLE) and multiple sclerosis (MS)". Cytokine & Growth Factor Reviews 13 (4-5): 403–12. doi:10.1016/S1359-6101(02)00025-4. PMID 12220553.
- Mocellin S, Panelli MC, Wang E, Nagorsen D, Marincola FM (Jan 2003). "The dual role of IL-10". Trends in Immunology 24 (1): 36–43. doi:10.1016/S1471-4906(02)00009-1. PMID 12495723.
- Roncarolo MG, Battaglia M, Gregori S (Jun 2003). "The role of interleukin 10 in the control of autoimmunity". Journal of Autoimmunity 20 (4): 269–72. doi:10.1016/S0896-8411(03)00047-7. PMID 12791310.
- Groux H, Cottrez F (Jun 2003). "The complex role of interleukin-10 in autoimmunity". Journal of Autoimmunity 20 (4): 281–5. doi:10.1016/S0896-8411(03)00044-1. PMID 12791313.
- Llorente L, Richaud-Patin Y (Jun 2003). "The role of interleukin-10 in systemic lupus erythematosus". Journal of Autoimmunity 20 (4): 287–9. doi:10.1016/S0896-8411(03)00043-X. PMID 12791314.
- Asadullah K, Sabat R, Friedrich M, Volk HD, Sterry W (Jun 2004). "Interleukin-10: an important immunoregulatory cytokine with major impact on psoriasis". Current Drug Targets. Inflammation and Allergy 3 (2): 185–92. doi:10.2174/1568010043343886. PMID 15180472.
- Stenvinkel P, Ketteler M, Johnson RJ, Lindholm B, Pecoits-Filho R, Riella M et al. (Apr 2005). "IL-10, IL-6, and TNF-alpha: central factors in the altered cytokine network of uremia--the good, the bad, and the ugly". Kidney International 67 (4): 1216–33. doi:10.1111/j.1523-1755.2005.00200.x. PMID 15780075.
- Copeland KF (Dec 2005). "Modulation of HIV-1 transcription by cytokines and chemokines". Mini Reviews in Medicinal Chemistry 5 (12): 1093–101. doi:10.2174/138955705774933383. PMID 16375755.
External links
- Interleukin-10 at the US National Library of Medicine Medical Subject Headings (MeSH)
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PDB gallery
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1ilk: INTERLEUKIN-10 CRYSTAL STRUCTURE REVEALS THE FUNCTIONAL DIMER WITH AN UNEXPECTED TOPOLOGICAL SIMILARITY TO INTERFERON GAMMA
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1j7v: HUMAN IL-10 / IL-10R1 COMPLEX
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1lk3: ENGINEERED HUMAN INTERLEUKIN-10 MONOMER COMPLEXED TO 9D7 FAB FRAGMENT
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1vlk: STRUCTURE OF VIRAL INTERLEUKIN-10
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1y6k: Crystal structure of human IL-10 complexed with the soluble IL-10R1 chain
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1y6m: Crystal structure of Epstein-Barr virus IL-10 complexed with the soluble IL-10R1 chain
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1y6n: Crystal structure of Epstein-Barr virus IL-10 mutant (A87I) complexed with the soluble IL-10R1 chain
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2h24: Crystal structure of human IL-10
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2ilk: CRYSTAL STRUCTURE OF HUMAN INTERLEUKIN-10 AT 1.6 ANGSTROMS RESOLUTION
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Cell signaling: cytokines
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| Description |
- Intercellular
- neuropeptides
- growth factors
- cytokines
- hormones
- Cell surface receptors
- ligand-gated
- enzyme-linked
- G protein-coupled
- immunoglobulin superfamily
- integrins
- neuropeptide
- growth factor
- cytokine
- Intracellular
- adaptor proteins
- GTP-binding
- MAP kinase
- Calcium signaling
- Lipid signaling
- Pathways
- hedgehog
- Wnt
- TGF beta
- MAPK ERK
- notch
- JAK-STAT
- apoptosis
- hippo
- TLR
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