Interleukin 10
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]
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Gene and protein structure [edit]
The IL-10 protein is a homodimer; each of its subunits is 178-amino-acid long.[2]
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).[3]
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.[4] The expression of IL-10 is minimal in unstimulated tissues and seems to require triggering by commensal or pathogenic flora.[5] 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.[6] IL-10 induction involves ERK1/2, p38 and NFkB signalling and transcriptional activation via promoter binding of the transcription factors NFkB and AP-1.[6] 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.[7] Additionally, IL-10 expression is extensively regulated at the post-transcriptional level, which may involve control of mRNA stability via AU-rich elements[8] and by microRNAs such as let-7[9] or miR-106.[10]
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 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.;[11] 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.[12]
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.[13]
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.
Interactions [edit]
IL-10 has been shown to interact with Interleukin 10 receptor, alpha subunit.[14][15][16][17][18]
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]
- ^ 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.
- ^ 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.
- ^ 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.
- ^ Said E. A., Trautmann L., Dupuy F., Zhang Y., Ancuta P., El-Fari M., Douek D., Haddad E., and Sekaly R.-P. (2010.) Programmed death-1-induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection., Nature Medicine, 452–459.
- ^ Li X, Mai J, Virtue A, 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 (March 2010). "The regulation of IL-10 production by immune cells.". Nat Rev Immunol 10 (3): 170–181. doi:10.1038/nri2711. PMID 20154735.
- ^ 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.
- ^ 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. PMID 10861064. Unknown parameter
|online ISSN=ignored (help) - ^ 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.
- ^ 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.
- ^ "Entrez Gene: IL10 interleukin 10".
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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]
- Bortesi L, Rossato M, Schuster F, Raven N, Stadlmann J, Avesani L, Falorni A, Bazzoni F, Bock R, Schillberg S, Pezzotti M (2009). "Viral and murine interleukin-10 are correctly processed and retain their biological activity when produced in tobacco". BMC Biotechnol. 9: 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". Annu. Rev. Immunol. 19: 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 Purif. 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 Rev. 13 (4–5): 403–12. doi:10.1016/S1359-6101(02)00025-4. PMID 12220553.
- Mocellin S, Panelli MC, Wang E, et al. (2004). "The dual role of IL-10". Trends Immunol. 24 (1): 36–43. doi:10.1016/S1471-4906(02)00009-1. PMID 12495723.
- Roncarolo MG, Battaglia M, Gregori S (2004). "The role of interleukin 10 in the control of autoimmunity". J. Autoimmun. 20 (4): 269–72. doi:10.1016/S0896-8411(03)00047-7. PMID 12791310.
- Groux H, Cottrez F (2004). "The complex role of interleukin-10 in autoimmunity". J. Autoimmun. 20 (4): 281–5. doi:10.1016/S0896-8411(03)00044-1. PMID 12791313.
- Llorente L, Richaud-Patin Y (2004). "The role of interleukin-10 in systemic lupus erythematosus". J. Autoimmun. 20 (4): 287–9. doi:10.1016/S0896-8411(03)00043-X. PMID 12791314.
- Asadullah K, Sabat R, Friedrich M, et al. (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, et al. (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 Int. 67 (4): 1216–33. doi:10.1111/j.1523-1755.2005.00200.x. PMID 15780075.
- Copeland KF (2006). "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 [edit]
- Interleukin-10 at the US National Library of Medicine Medical Subject Headings (MeSH)
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