Interleukin 10 and interleukin 10 receptor in paediatric inflammatory bowel disease: from bench to bedside lesson
Journal of Inflammation volume 18, Article number: 13 (2021)
The differences between adults and children in inflammatory bowel disease (IBD) phenotype, severity, complications, co-morbidities, and response to the therapy resulted in the extraction of paediatric IBD. It has been revealed that the substantial role in the development of IBD in children under 6 years of age plays a single genetic mutation (monogenic IBD). On the other hand, in older children and adolescents IBD is usually associated with number of interactions between susceptibility loci (polygenic IBD).
Until now there have been described about 60 monogenic defects which affect the variety of immune mechanisms in IBD pathogenesis including epithelial barrier, function of neutrophil granulocytes and phagocytes, T- and B-cell selection and activation, immune inhibitory mechanisms, or apoptosis. Il-10 is an anti-inflammatory cytokine which modulates innate and adaptive immunity affecting expression of pro-inflammatory molecules and function of the variety of immune cells. Patients with identified defects in Il-10 pathway manifest with life-threating colitis with perianal lesions which occurs within first months of life. Allogenic hematopoietic stem cell transplantation is curative therapy in children with Il-10 signalling defects.
Clinical awareness of Il-10 signalling defects enables early recognition and prompt management of the disease.
Background: overview of paediatric inflammatory bowel disease
Inflammatory bowel disease (IBD) is a group of disorders characterized by a chronic relapsing inflammation of gastrointestinal tract. Pathogenesis of IBD involves a complex interplay between genetic susceptibility, environmental factors, dysbiosis and immune dysregulation . However, the exact mechanisms of IBD development remain unclear.
The differences in IBD phenotype, severity, complications, co-morbidities and response to the therapy between adults and children resulted in the extraction of paediatric IBD . Paediatric onset of IBD refers to patients with the disease onset prior to 17 years of age. According to patients’ age at IBD onset paediatric IBD may be subdivided into:
early onset IBD (EOIBD) recognized in children younger than 10 years of age,
very early onset IBD (VEOIBD) recognized in children younger than 6 years of age,
infantile (toddler) onset IBD recognized in children younger than 2 years of age and
neonatal IBD recognized in children during the first 28 days of age .
It has been observed that a single genetic mutation plays the substantial role in the development of very early onset of IBD (monogenic IBD) [2, 3]. On the other hand, in older children and adolescents the overall risk of IBD is associated with number of interactions between susceptibility loci [2, 3]. Kaser et al. suggested that polygenic IBD development is significantly affected by environmental factors .
That fact may explain diversity in IBD phenotype between children with VEOIBD from those with older-onset IBD and may lead to identification of novel target therapeutic options and tailored-made approach to paediatric IBD patients .
Until now there have been described about 60 monogenic defects  which affect the variety of immune mechanisms in IBD pathogenesis including epithelial barrier, function of neutrophil granulocytes and phagocytes, T- and B-cell selection and activation, immune inhibitory mechanisms or apoptosis [2, 5]. The aim of our study is to present clinical aspects of defects in Il-10 signalling in children with early onset of IBD.
Interleukin-10 signalling pathway
Il-10 is encoded by the Il-10 gene located on the long arm of chromosome 1 (region 1q32) . Il-10 is a 36 kDa homodimer of two 160 amino acid polypeptide chains . Each subunit consists of six helices which are connected by two loops and three turns [7, 9]. Il-10 is expressed by the wide range of innate and adaptive immune cells including T and B lymphocytes, monocytes, macrophages, natural killer cells (NK), neutrophils, mast cells, dendritic cells and epithelial cells .
Il-10 binds to the tetrameric receptor (Il-10R) which is formed of two α-chains of Il-10 receptor 1 (Il-10R1) and two β-chains of Il-10 receptor 2 (Il-10R2) [7, 9,10,11]. Each of these chains consists of extracellular, transmembrane and intracellular domain . Il-10 receptor 1 is specific for Il-10 binding, while Il-10 receptor 2 may be a signal transducing subunit of other representatives of Il-10 cytokine family [11, 12].
The binding of Il-10 to its receptor activates Janus kinase 1 (JAK1) and tyrosine kinase 2 (Tyk2). Both kinases phosphorylate Il-10R1 which subsequently phosphorylates and recruits signal transducer and activator of transcription 3 (STAT3). Phosphorylation of STAT3 result in its dimerization, translocation to the nucleus and promotion of target genes’ transcription. Eventually a down-stream signalling cascade leads to expression of anti-inflammatory effectors [8, 10,11,12,13].
Il-10 is a crucial anti-inflammatory cytokine which modulates innate and adaptive immunity affecting expression of proinflammatory molecules and function of the variety of immune cells. Il-10 inhibits the maturation and antigen-presenting cell function of dendritic cells through suppression of Iκβ kinase (IKK), serine-threonine kinase Akt and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκβ) . Il-10 produced by dendritic cells causes ubiquitination and degradation of myeloid differentiation factor (MyD)88-dependent signalling molecules including Il-1 receptor-associated kinase IRAK4, IRAK1 and TNF-receptor associated factor (TRAF)6, to inhibit TLR-mediated MyD88-dependent pathway . That process contributes in the negative regulation of the expression of inflammatory cytokines including Il-6, Il-1β and TNF-α . Il-10 suppresses Th1/Th17 cell-mediated adaptive immune response [16, 17]. In response to Il-10 the expression of major histocompatibility complex II (MHC class II) is reduced on monocytes, macrophages and dendritic cells and increased on B lymphocytes [8, 16]. Moreover, Il-10 enhances secretion of immunoglobulins and immunoglobulin class-switching in B cells .
Although Il-10 down-regulates expression of inflammatory mediators and inhibits antigen presentation, it stimulates proliferation and up-regulates activation of NK-cells, CD8+ T-cells, B lymphocytes and mast cells [8, 16, 18]. Table 1 presents summary of main functions of Il-10 in host immune response [8, 16, 18, 19].
Interleukin-10 knockout mouse model of inflammatory bowel disease
In the past decades, it has been shown that Il-10 deficient mice with lacking functional Il-10 (Il-10−/−) or Il-10 R2 subunit (Il-10 Rb−/−) developed spontaneous enterocolitis [20, 21] which resulted from unbalanced Th1/Th17 response, excessive release of proinflammatory cytokines (mainly Il-12, Il-13, Il-17, Il-23, IFNγ) and failure in homeostatic relationship between microbiota and the host [16, 17].
Interleukin-10-deficient mice colitis is a multi-hit model of colitis which involves genetic factor, immune disturbances and alterations of gut microbiota . It has been shown that the presence of resident enteric bacteria is essential for the development of spontaneous colitis in Il-10-deficient mice, while germfree Il-10-deficient mice had no evidence of colitis or immune system activation [17, 22]. Specific pathogens including Enterococcus faecalis, Escherichia coli, Helicobacter hepaticus or Murine Norovirus appear to act as colitogenic triggers which promote inflammation in Il-10-deficient mice [17, 23,24,25,26]. Nevertheless, Lactobacillus salivarius 433,118 and Bifidobacterium infantis 35,624 were found to attenuate colitis in Il-10-deficient mice . There are also known some strain-specific genetic factors which may determine mucosal immune response . For example, it has been reported that a major colitogenic loci Cdcs1 may modify the response to inflammation induced by Helicobacter hepaticus in the murine model . On the other hand, dysbiosis may also alter strain-specific colitis susceptibility and host immune response [17, 25].
In conventional environment chronic enterocolitis in Il-10 deficient mice occurs by 2–3 months of age, soon after weaning and features transmural involvement and mucosal discontinuity [17, 20, 28]. Inflammatory cells including lymphocytes, plasmocytes, macrophages, eosinophils, and neutrophils infiltrate into the lamina propria and submucosa. Other pathological lesions of enterocolitis in Il-10 deficient mice are as follows epithelial hyperplasia, mucin depletion, crypt abscesses, ulcers, and thickening of bowel wall [17, 20, 28].
Interleukin-10 pathway defects in humans
Defects of Il-10 and Il-10 receptors are monogenic autosomal recessive diseases with 100% penetrance [2, 29]. Since first description of mutations in genes Il-10RA and Il-10RB in patients with early-onset colitis in 2009, about 70 cases of Il-10/Il-l0R deficient patients with IBD phenotype have been identified [11,12,13]. Although the frequency of Il-10 and Il-10 receptor defects is not established, several studies reported data on their prevalence in cohorts of children with IBD [30, 31]. Among 66 children with early-onset of IBD there were identified 16 (24.2%) with mutations in Il-10-related genes including 8 (12.1%) with mutation in Il-10RB gene, 5 (7.6%) with mutation in Il-10RA gene and 3 (4.5%) with mutation in Il-10 gene . Genetic screening in a group of 62 IBD children with disease onset before the age of 2 years revealed 5 (8%) cases of Il-10 or Il-10R genes’ mutations i.e., 2 (3.2%) with Il-10 gene mutation, 2 (3.2%) with Il-10RB gene mutation and 1 (1.6%) with Il-10RA gene mutation .
Defects in Il-10 signalling pathway manifest as a Crohn’s disease-like conditions [2, 12]. Although no clear genotype-phenotype correlations have been established, there are some differences in clinical picture of Il-10 and Il-10R defects. Patients with identified mutations in Il-10 gene in the first 3 months of life presented with colitis with perianal lesions which was resistant to complex therapy approach (steroids, immunosuppression, anti-TNF-alfa agents). The disease is manifested as a severe bloody diarrhoea which may lead to the weight loss and growth impairment [12, 32]. Patients suffer also from the presence of perianal fistulas or abscesses [12, 32]. One patient with Il-10 deficiency experienced also oral ulcers and moderate hearing loss . In general children with Il-10 deficiency did not exhibit any extraintestinal manifestations [2, 12]. Among patients with mutations in Il-10 gene there were no significant alterations in the level of immunoglobulins, apart from increased level of IgA and IgM in one case [12, 30].
Children with mutations in Il-10RA and Il-10RB genes manifested with severe, intractable granulomatous enterocolitis with perianal lesions and penetrating behaviour within first months of life [12, 30]. In contrast to Il-10 deficiency, Il-10 receptor deficiencies are associated with some extraintestinal manifestations like folliculitis, eczema, arthritis, or autoimmune hepatitis [2, 12, 30]. Possible causes of the fact that folliculitis may indicate Il-10RB deficiency include the fact that beta chain of Il-10 receptor is expressed on keratinocytes and secondly it may be a signal transducing subunit of the receptors for other interleukins [12, 32].
Recurrent infections were frequently noted in that group of patients . There have been also described cases of children with Il-10RB defect who revealed B-cell lymphoma [12, 30]. It has been suggested that since IL-10RB is a part of λ-interferon involved in antiviral defence its deficiency and immunosuppressive therapy may increase risk of viral infections and EBV-induced lymphomas [12, 32].
Several patients with mutations in Il-10RA or Il-10RB genes had increased level of immunoglobulins IgA, IgG or IgM .
Similarly to IBD associated with mutations in Il-10 gene, Il-10 receptor deficiencies are also refractory to conventional immunosuppressive therapy [12, 30]. To date the only effective documented curative therapy in children with Il-10 signalling defects is allogenic hematopoietic stem cell transplantation [2, 12, 30, 33].
It must be also noted that there have been reported several polymorphisms in Il-10 gene which are associated with increased risk of IBD in adults [8, 34]. However, this issue is beyond the scope of this review.
Interleukin 10 - is it a therapeutic option in inflammatory bowel disease?
Since Il-10 appears to play a key role in regulation of inflammatory mediators and antigen presentation, it has been suggested as a potent anti-inflammatory therapy in IBD. Although some studies on recombinant human Il-10 reported clinical and endoscopic improvement as a result of Il-10 supplementation [35, 36], the systematic review by Buruiana et al. showed that Il-10 is not effective in the induction of remission in Crohn’s disease .
Several potential reasons of lack of Il-10 efficacy have been proposed including low stability and poor bioavailability of the drug . Another explanation of this phenomenon may be that immunosuppressive action of Il-10 is revealed only under certain conditions or counterbalanced by its proinflammatory properties [8, 38]. It has been also suggested that Il-10 may not have ability to reverse IBD, but it may prevent IBD development [8, 38]. Last but not least, Il-10 may be insufficient to counter impaired immune response in IBD . These aspects may be addressed in future studies on Il-10 pathway as a therapeutic target in IBD.
Monogenic genes’ defects appear to be causal factors underlying pathogenesis of paediatric IBD with early and very early onset. There are described about 60 monogenic defects which affect the variety of immune mechanisms in IBD pathogenesis including defects in Il-10 signalling . Il-10 is a crucial anti-inflammatory cytokine which modulates innate and adaptive immunity affecting expression of proinflammatory molecules and function of the variety of immune cells. Patients with identified defects in Il-10 pathway manifest with severe colitis with perianal lesions which occurs within first months of life and is resistant to standard therapy. Clinical awareness of Il-10 signalling defects enables early recognition and prompt treatment of the disease.
Availability of data and materials
Early onset inflammatory bowel disease
Inflammatory bowel disease
Interleukin 10 Receptor
I1–1 receptor-associated kinase
Janus kinase 1
- MHC class II:
Major histocompatibility complex II
Natural killer cells
Nuclear factor kappa-light-chain-enhancer of activated B cells
Signal transducer and activator of transcription 3
TNF-receptor associated factor
Tyrosine kinase 2
Very early onset of inflammatory bowel disease
Zhang YZ, Li YY. Inflammatory bowel disease: pathogenesis. World J Gastroenterol. 2014;20(1):91–9. https://doi.org/10.3748/wjg.v20.i1.91.
Uhlig HH, Schwerd T, Koletzko S, et al. The diagnostic approach to monogenic very early onset inflammatory bowel disease. Gastroenterology. 2014;147(5):990–1007.e3. https://doi.org/10.1053/j.gastro.2014.07.023.
Kaser A, Zeissig S, Blumberg RS. Genes and environment: how will our concepts on the pathophysiology of IBD develop in the future? Dig Dis. 2010;28(3):395–405. https://doi.org/10.1159/000320393.
Kelsen JR, Baldassano RN. The role of monogenic disease in children with very early onset inflammatory bowel disease. Curr Opin Pediatr. 2017;29(5):566–71. https://doi.org/10.1097/MOP.0000000000000531.
Shim JO. Recent advance in very early onset inflammatory bowel disease. Pediatr Gastroenterol Hepatol Nutr. 2019;22(1):41–9. https://doi.org/10.5223/pghn.2019.22.1.41.
Shouval DS, Ouahed J, Biswas A, et al. Interleukin 10 receptor signaling: master regulator of intestinal mucosal homeostasis in mice and humans Dror. Adv Immunol. 2016;122:177–210. https://doi.org/10.1016/B978-0-12-800267-4.00005-5.Interleukin.
Walter MR. The molecular basis of IL-10 function: from receptor structure to the onset of signaling. Curr Top Microbiol Immunol. 2014;380:191–212. https://doi.org/10.1007/978-3-662-43492-5.
Marlow GJ, Van GD, Ferguson LR, et al. Why interleukin-10 supplementation does not work in Crohn ’ s disease patients. World J Gastroenterol. 2013;19(25):3931–41. https://doi.org/10.3748/wjg.v19.i25.3931.
Zdanov A. Structural features of the Interleukin-10 family of cytokines. Curr Pharm Des. 2004;10:3873–84.
Shah N, Kammermeier J, Elawad M. Interleukin-10 and Interleukin-10 – receptor defects in inflammatory bowel disease. Curr Allergy Asthma Rep. 2012;12:373–9. https://doi.org/10.1007/s11882-012-0286-z.
Zhu L, Shi T, Zhong C, Wang Y, Chang M, Liu X. IL-10 and IL-10 receptor mutations in very early onset inflammatory bowel disease. Gastroenterol Res. 2017;10(2):65–9.
Engelhardt KR, Grimbacher B. IL-10 in humans: lessons from the gut, IL-10/IL-10 receptor deficiencies, and IL-10 polymorphisms. In: Current topics in microbiology and immunology Interleukin-10 in health and disease; 2014. p. 1–18.
Lin Z, Sci BJ, Res T, Lin TR, Floros J, Lin Z. Pediatric inflammatory bowel Disease : a review of immune homeostasis and genetics with an emphasis on the IL-10 pathway. J Sci Tech Res. 2018;2(1):1–9. https://doi.org/10.26717/BJSTR.2018.02.000713.
Bhattacharyya S, Sen P, Wallet M, Long B, Baldwin ASJ, Tisch R. Immunoregulation of dendritic cells by IL-10 is mediated through suppression of the PI3K/Akt pathway and of IkappaB kinase activity. Blood. 2004;104(4):1100–9. https://doi.org/10.1182/blood-2003-12-4302.
Chang J, Kunkel SL, Chang C-H. Negative regulation of MyD88-dependent signaling by IL-10 in dendritic cells. Proc Natl Acad Sci U S A. 2009;106(43):18327–32. https://doi.org/10.1073/pnas.0905815106.
Paul G, Khare V, Gasche C. Inflamed gut mucosa : downstream of interleukin-10. Eur J Clin Investig. 2011;42(1):95–109. https://doi.org/10.1111/j.1365-2362.2011.02552.x.
Keubler LM, Buettner M, Häger C, Bleich A. A multihit model: colitis lessons from the Interleukin-10-deficient mouse. Inflamm Bowel Dis. 2015;21(8):1967–75. https://doi.org/10.1097/MIB.0000000000000468.
Iyer SS, Cheng G. Role of interleukin 10 transcriptional regulation in inflammation and autoimmune disease. Crit Rev Immunol. 2012;32(1):23–63.
Cho MJ, Ellebrecht CT, Payne AS. The dual nature of interleukin-10 in pemphigus vulgaris. Cytokine. 2015;73(2):335–41. https://doi.org/10.1016/j.cyto.2014.11.002.
Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993;75(2):263–74.
Spencer SD, Di Marco F, Hooley J, et al. The orphan receptor CRF2-4 is an essential subunit of the interleukin 10 receptor. J Exp Med. 1998;187(4):571–8.
Sellon RK, Tonkonogy S, Schultz M, et al. Resident enteric bacteria are necessary for development of spontaneous colitis and immune system activation in interleukin-10-deficient mice. Infect Immun. 1998;66(11):5224–31.
Kim SC, Tonkonogy SL, Albright CA, et al. Variable phenotypes of enterocolitis in interleukin 10-deficient mice monoassociated with two different commensal bacteria. Gastroenterology. 2005;128(4):891–906.
Burich A, Hershberg R, Waggie K, et al. Helicobacter-induced inflammatory bowel disease in IL-10- and T cell-deficient mice. Am J Physiol Gastrointest Liver Physiol. 2001;281(3):G764–78. https://doi.org/10.1152/ajpgi.2001.281.3.G764.
Buchler G, Wos-Oxley ML, Smoczek A, et al. Strain-specific colitis susceptibility in IL10-deficient mice depends on complex gut microbiota-host interactions. Inflamm Bowel Dis. 2012;18(5):943–54. https://doi.org/10.1002/ibd.21895.
Basic M, Keubler LM, Buettner M, et al. Norovirus triggered microbiota-driven mucosal inflammation in interleukin 10-deficient mice. Inflamm Bowel Dis. 2014;20(3):431–43. https://doi.org/10.1097/01.MIB.0000441346.86827.ed.
McCarthy J, O’Mahony L, O’Callaghan L, et al. Double blind, placebo controlled trial of two probiotic strains in interleukin 10 knockout mice and mechanistic link with cytokine balance. Gut. 2003;52(7):975–80. https://doi.org/10.1136/gut.52.7.975.
Gomes-Santos AC, Moreira TG, Castro-Junior AB, et al. New insights into the immunological changes in IL-10-deficient mice during the course of spontaneous inflammation in the gut mucosa. Clin Dev Immunol. 2012;2012:560817. https://doi.org/10.1155/2012/560817.
Glocker E-O, Kotlarz D, Klein C, Shah N, Grimbacher B. IL-10 and IL-10 receptor defects in humans. Ann N Y Acad Sci. 2011;1246(1):102–7. https://doi.org/10.1111/j.1749-6632.2011.06339.x.
Kotlarz D, Beier R, Murugan D, et al. Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy. Gastroenterology. 2012;143(2):347–55. https://doi.org/10.1053/j.gastro.2012.04.045.
Kammermeier J, Dziubak R, Pescarin M, et al. Phenotypic and genotypic characterisation of inflammatory bowel disease presenting before the age of 2 years. J Crohns Colitis. 2017;11(1):60–9. https://doi.org/10.1093/ecco-jcc/jjw118.
Pigneur B, Escher J, Elawad M, et al. Phenotypic characterization of very early-onset IBD due to mutations in the IL10, IL10 receptor alpha or beta gene: a survey of the genius working group. Inflamm Bowel Dis. 2013;19(13):2820–8. https://doi.org/10.1097/01.MIB.0000435439.22484.d3.
Engelhardt KR, Shah N, Faizura-Yeop I, et al. Clinical outcome in IL-10– and IL-10 receptor–deficient patients with or without hematopoietic stem cell transplantation. J Allergy Clin Immunol. 2013;131(3):825–830.e9. https://doi.org/10.1016/j.jaci.2012.09.025.
Ouyang W, O’Garra A. IL-10 Family Cytokines IL-10 and IL-22: from Basic Science to Clinical Translation. Immunity. 2019;50(4):871–91. https://doi.org/10.1016/j.immuni.2019.03.020.
van Deventer SJ, Elson CO, Fedorak RN. Multiple doses of intravenous interleukin 10 in steroid-refractory Crohn’s disease. Crohn’s disease study group. Gastroenterology. 1997;113(2):383–9.
Fedorak RN, Gangl A, Elson CO, et al. 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. Gastroenterology. 2000;119(6):1473–82.
Buruiana FE, Sola I, Alonso-Coello P. Recombinant human interleukin 10 for induction of remission in Crohn’s disease. Cochrane Database Syst Rev. 2010;11:CD005109. https://doi.org/10.1002/14651858.CD005109.pub3.
Bilsborough J, Targan SR, Snapper SB. Therapeutic targets in inflammatory bowel disease: current and future. Am J Gastroenterol Suppl. 2016;3:37.
This research received no external funding. The APC was funded by the Medical University of Lublin (scientific grant to E.P-K. No DS406).
Ethics approval and consent to participate
Consent for publication
The authors declare that they have no conflict of interest.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Krawiec, P., Pawłowska-Kamieniak, A. & Pac-Kożuchowska, E. Interleukin 10 and interleukin 10 receptor in paediatric inflammatory bowel disease: from bench to bedside lesson. J Inflamm 18, 13 (2021). https://doi.org/10.1186/s12950-021-00279-3
- Crohn’s disease
- Ulcerative colitis