Interleukin 10

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Interleukin 10
IL10 Crystal Structure.rsh.png
PDB rendering based on 2H24.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols IL10 ; CSIF; GVHDS; IL-10; IL10A; TGIF
External IDs OMIM124092 MGI96537 HomoloGene478 GeneCards: IL10 Gene
RNA expression pattern
PBB GE IL10 207433 at.png
More reference expression data
Orthologs
Species Human Mouse
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:
206.94 – 206.95 Mb
Chr 1:
131.02 – 131.02 Mb
PubMed search [1] [2]

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 molecules.[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]

Gene and protein structure[edit]

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[edit]

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 autokrine 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[edit]

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.

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]

Interactions[edit]

IL-10 has been shown to interact with Interleukin 10 receptor, alpha subunit.[18][19][20][21][22]

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[edit]

  1. ^ 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. 
  2. ^ a b Mosser DM, Zhang X (2008). "Interleukin-10: new perspectives on an old cytokine". Immunol. Rev. 226: 205–18. doi:10.1111/j.1600-065X.2008.00706.x. PMC 2724982. PMID 19161426. 
  3. ^ Zdanov A, Schalk-Hihi C, Gustchina A, Tsang M, Weatherbee J, Wlodawer A (June 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. 
  4. ^ Pestka S, Krause CD, Sarkar D, Walter MR, Shi Y, Fisher PB (2004). "Interleukin-10 and related cytokines and receptors". Annu. Rev. Immunol. 22: 929–79. doi:10.1146/annurev.immunol.22.012703.104622. PMID 15032600. 
  5. ^ 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 (2010). "Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection". Nat. Med. 16 (4): 452–9. doi:10.1038/nm.2106. PMC 4229134. PMID 20208540. 
  6. ^ Li X, Mai J, Virtue A, Yin Y, Gong R, Sha X, Gutchigian S, Frisch A, Hodge I, Jiang X, Wang H, Yang XF (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. 
  7. ^ a b Saraiva M, O'Garra A (March 2010). "The regulation of IL-10 production by immune cells.". Nat Rev Immunol 10 (3): 170–181. doi:10.1038/nri2711. PMID 20154735. 
  8. ^ Hammer M, Mages J, Dietrich H, Schmitz F, Striebel F, Murray PJ, Wagner H, Lang R (March 2010). "Control of dual-specificity phosphatase-1 expression in activated macrophages by IL-10.". Eur J Immunol 35 (10): 2991–3001. doi:10.1002/eji.200526192. PMID 16184516. 
  9. ^ Powell MJ, Thompson SA, Tone Y, Waldmann H, Tone M (July 2000). "Posttranscriptional regulation of IL-10 gene expression through sequences in the 3'-untranslated region.". J Immunol 165 (1): 292–296. doi:10.4049/jimmunol.165.1.292. ISSN 1550-6606. PMID 10861064. 
  10. ^ 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.". EMBO J 30 (10): 1977–1989. doi:10.1038/emboj.2011.94. PMID 21468030. 
  11. ^ Sharma A, Kumar M, Aich J, Hariharan M, Brahmachari SK, Agrawal A, Ghosh B (April 2009). "Posttranscriptional regulation of interleukin-10 expression by hsa-miR-106a.". Proc Natl Acad Sci U S A 106 (14): 5761–5766. doi:10.1073/pnas.0808743106. PMID 19307576. 
  12. ^ "Entrez Gene: IL10 interleukin 10". 
  13. ^ Braat H, Rottiers P, Hommes DW, Huyghebaert N, Remaut E, Remon JP, van Deventer SJ, Neirynck S, Peppelenbosch MP, Steidler L (June 2006). "A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn's disease". Clin. Gastroenterol. Hepatol. 4 (6): 754–9. doi:10.1016/j.cgh.2006.03.028. PMID 16716759. 
  14. ^ Grimbaldeston MA, Nakae S, Kalesnikoff J, Tsai M, Galli SJ (October 2007). "Mast cell-derived interleukin 10 limits skin pathology in contact dermatitis and chronic irradiation with ultraviolet B". Nat. Immunol. 8 (10): 1095–104. doi:10.1038/ni1503. PMID 17767162. 
  15. ^ 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 (2013). "Interleukin 10 knockout frail mice develop cardiac and vascular dysfunction with increased age". Exp. Gerontol. 48 (2): 128–35. doi:10.1016/j.exger.2012.11.001. PMC 3744178. PMID 23159957. 
  16. ^ Ostrowski K, Schjerling P, Pedersen BK (2000). "Physical activity and plasma interleukin-6 in humans--effect of intensity of exercise". Eur. J. Appl. Physiol. 83 (6): 512–5. doi:10.1007/s004210000312. PMID 11192058. 
  17. ^ Ostrowski K, Rohde T, Asp S, Schjerling P, Pedersen BK (1999). "Pro- and anti-inflammatory cytokine balance in strenuous exercise in humans". J. Physiol. (Lond.). 515 ( Pt 1): 287–91. doi:10.1111/j.1469-7793.1999.287ad.x. PMC 2269132. PMID 9925898. 
  18. ^ Ho AS, Liu Y, Khan TA, Hsu DH, Bazan JF, Moore KW (December 1993). "A receptor for interleukin 10 is related to interferon receptors". Proc. Natl. Acad. Sci. U.S.A. 90 (23): 11267–71. doi:10.1073/pnas.90.23.11267. PMC 47963. PMID 8248239. 
  19. ^ Josephson K, Logsdon NJ, Walter MR (July 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. 
  20. ^ Tan JC, Braun S, Rong H, DiGiacomo R, Dolphin E, Baldwin S, Narula SK, Zavodny PJ, Chou CC (May 1995). "Characterization of recombinant extracellular domain of human interleukin-10 receptor". J. Biol. Chem. 270 (21): 12906–11. doi:10.1074/jbc.270.21.12906. PMID 7759550. 
  21. ^ Josephson K, McPherson DT, Walter MR (December 2001). "Purification, crystallization and preliminary X-ray diffraction of a complex between IL-10 and soluble IL-10R1". Acta Crystallogr. D Biol. Crystallogr. 57 (Pt 12): 1908–11. doi:10.1107/S0907444901016249. PMID 11717514. 
  22. ^ 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". Eur. J. Biochem. 262 (1): 134–41. doi:10.1046/j.1432-1327.1999.00363.x. PMID 10231374. 

Further reading[edit]

External links[edit]