Interleukin 10
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| Location (UCSC) | Chr 1: 206.77 – 206.77 Mb | Chr 1: 130.95 – 130.95 Mb | |||||||
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Interleukin 10 (IL-10), also known as human cytokine synthesis inhibitory factor (CSIF), is an anti-inflammatory cytokine. In humans, interleukin 10 is encoded by the IL10 gene.[5] IL-10 signals through a receptor complex consisting of two IL-10 receptor-1 and two IL-10 receptor-2 proteins.[6] 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.[6]
Gene and protein structure
The IL-10 protein is a homodimer; each of its subunits is 178-amino-acid long.[7]
IL-10 is classified as a class-2 cytokine, a set of cytokines including
Expression and synthesis
In humans, IL-10 is encoded by the IL10 gene, which is located on
Function
IL-10 is a cytokine with multiple,
Discovered in 1991,
Effect on tumors
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
A study in mice has shown that IL-10 is also produced by
IL-10 is capable of inhibiting synthesis of pro-inflammatory cytokines such as
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 the
Lower levels of IL-10 have been observed in individuals diagnosed with
In melanoma cell lines, IL-10 modulates the surface expression of NKG2D ligands.[43]
In addition, Forkhead box protein 3 (
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
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
Further to these data, a Phase I immunoncology clinical trial is currently being conducted to assess the therapeutic capacity of
Interactions
IL-10 has been shown to
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 GRCh38: Ensembl release 89: ENSG00000136634 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000016529 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ S2CID 30126106.
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- ^ "Entrez Gene: IL10 interleukin 10".
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- ^ a b c d Infante JR, Naing A, Papadopoulos KP, Autio KA, Ott PA, Wong DJ, Falchook GS, Patel MR, Pant S (2015-05-20). "A first-in-human dose escalation study of PEGylated recombinant human IL-10 (AM0010) in advanced solid tumors". ASCO Meeting Abstracts. 33 (15_suppl): 3017. Archived from the original on 2015-12-22. Retrieved 2015-12-10.
- ^ Early Data Supports Phase 3 Trial of Pegilodecakin as Possible Treatment for Advanced Pancreatic Cancer
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Further reading
- Bortesi L, Rossato M, Schuster F, Raven N, Stadlmann J, Avesani L, Falorni A, Bazzoni F, Bock R, Schillberg S, Pezzotti M (March 2009). "Viral and murine interleukin-10 are correctly processed and retain their biological activity when produced in tobacco". BMC Biotechnology. 9 (1): 22. PMID 19298643.
- Zhu H, Wang Z, Yu J, Yang X, He F, Liu Z, Che F, Chen X, Ren H, Hong M, Wang J (March 2019). "Role and mechanisms of cytokines in the secondary brain injury after intracerebral hemorrhage". Prog. Neurobiol. 178: 101610. S2CID 85495400.
- 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. PMID 11244051.
- Girndt M (2003). "Humoral immune responses in uremia and the role of IL-10". Blood Purification. 20 (5): 485–8. S2CID 46867122.
- 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. PMID 12220553.
- Mocellin S, Panelli MC, Wang E, Nagorsen D, Marincola FM (January 2003). "The dual role of IL-10". Trends in Immunology. 24 (1): 36–43. PMID 12495723.
- Roncarolo MG, Battaglia M, Gregori S (June 2003). "The role of interleukin 10 in the control of autoimmunity". Journal of Autoimmunity. 20 (4): 269–72. PMID 12791310.
- Groux H, Cottrez F (June 2003). "The complex role of interleukin-10 in autoimmunity". Journal of Autoimmunity. 20 (4): 281–5. PMID 12791313.
- Llorente L, Richaud-Patin Y (June 2003). "The role of interleukin-10 in systemic lupus erythematosus". Journal of Autoimmunity. 20 (4): 287–9. PMID 12791314.
- Asadullah K, Sabat R, Friedrich M, Volk HD, Sterry W (June 2004). "Interleukin-10: an important immunoregulatory cytokine with major impact on psoriasis". Current Drug Targets. Inflammation and Allergy. 3 (2): 185–92. PMID 15180472.
- Stenvinkel P, Ketteler M, Johnson RJ, Lindholm B, Pecoits-Filho R, Riella M, Heimbürger O, Cederholm T, Girndt M (April 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. PMID 15780075.
- Chang CF, Wan J, Li Q, Renfroe SC, Heller NM, Wang J (July 2017). "Alternative activation-skewed microglia/macrophages promote hematoma resolution in experimental intracerebral hemorrhage". Neurobiol. Dis. 103: 54–69. PMID 28365213.
- Copeland KF (December 2005). "Modulation of HIV-1 transcription by cytokines and chemokines". Mini Reviews in Medicinal Chemistry. 5 (12): 1093–101. PMID 16375755.
External links
Media related to Interferons or interleukin-10 (IL-10) at Wikimedia Commons- Interleukin-10 at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
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