Current Allergy and Asthma Reports

, Volume 12, Issue 5, pp 373–379 | Cite as

Interleukin-10 and Interleukin-10–Receptor Defects in Inflammatory Bowel Disease

  • Neil Shah
  • Jochen Kammermeier
  • Mamoun Elawad
  • Erik-Oliver Glocker
Immune Deficiency and Dysregulation (DP Huston, Section Editor)

Abstract

Inflammatory bowel disease (IBD) is a chronic inflammatory disease characterized by abdominal pain, bloody diarrhoea, and malabsorption leading to weight loss. It is considered the result of inadequate control of an excessive reaction of the immune system to the resident flora of the gut. Like other primary immunodeficiencies, IL-10 and IL-10 receptor (IL10R) deficiency present with IBD and demonstrate the sensitivity of the intestine to any changes of the immune system. Both IL-10 and IL10R deficiency cause severe early-onset enterocolitis and can be successfully treated by hematopoietic stem cell transplantation (HSCT).

Keywords

Interleukin-10 IL-10 IL-10 receptor Mutation STAT3 Inflammatory bowel disease Colitis 

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Podolsky DK. Inflammatory bowel disease. N Engl J Med. 2002;347:417–29.PubMedCrossRefGoogle Scholar
  2. 2.
    Sawczenko A, Sandhu BK. Presenting features of inflammatory bowel disease in Great Britain and Ireland. Arch Dis Child. 2003;88:995–1000.PubMedCrossRefGoogle Scholar
  3. 3.
    Xavier RJ, Podolsky DK. Unraveling the pathogenesis of inflammatory bowel disease. Nature. 2007;448:427–34.PubMedCrossRefGoogle Scholar
  4. 4.
    Engel MA, Neurath MF. New pathophysiological insights and modern treatment of IBD. J Gastroenterol. 2010;45:571–83.PubMedCrossRefGoogle Scholar
  5. 5.
    Mizoguchi A, Mizoguchi E. Inflammatory bowel disease, past, present, and future: lessons from animal models. J Gastroenterol. 2008;43:1–17.PubMedCrossRefGoogle Scholar
  6. 6.
    Elson CO, Cong Y, McCracken VJ, Dimmitt RA, Lorenz RG, Weaver CT. Experimental models of inflammatory bowel disease reveal innate, adaptive, and regulatory mechanisms of host dialogue with the microbiota. Immunol Rev. 2005;206:60–76.CrossRefGoogle Scholar
  7. 7.
    Cho JH. The genetics and immunopathogenesis of inflammatory bowel disease. Nat Rev Immunol. 2008;8:458–66.PubMedCrossRefGoogle Scholar
  8. 8.
    Van Limbergen J, Wilson DC, Satsangi J. The genetics of Crohn's disease. Annu Rev Genomics Hum Genet. 2009;10:89–116.PubMedCrossRefGoogle Scholar
  9. 9.
    Thrasher AJ, Burns SO. WASP: a key immunological multitasker. Nat Rev Immunol. 2010;10:182–92.PubMedCrossRefGoogle Scholar
  10. 10.
    Cheng LE, Kanwar B, Tcheurekdjian H, Grenert JP, Muskat M, Heyman MB, et al. Persistent systemic inflammation and atypical enterocolitis in patients with NEMO syndrome. Clin Immunol. 2009;132:124–31.PubMedCrossRefGoogle Scholar
  11. 11.
    Marks DJ, Miyagi K, Rahman FZ, Novelli M, Bloom SL, Segal AW. Inflammatory bowel disease in CGD reproduces the clinicopathological features of Crohn's disease. Am J Gastroenterol. 2009;104:117–24.PubMedCrossRefGoogle Scholar
  12. 12.
    Marsh RA, Madden L, Kitchen BJ, Mody R, McClimon B, Jordan MB, et al. XIAP deficiency: a unique primary immunodeficiency best classified as X-linked familial hemophagocytic lymphohistiocytosis and not as X-linked lymphoproliferative disease. Blood. 2010;116:1079–82.PubMedCrossRefGoogle Scholar
  13. 13.
    Pachlopnik Schmid J, Canioni D, Moshous D, Touzot F, Mahlaoui N, Hauck F, et al. Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) vs type 2 (XLP-2/XIAP deficiency). Blood. 2011;117:1522–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Moraes-Vasconcelos D, Costa-Carvalho BT, Torgerson TR, Ochs HD. Primary immune deficiency disorders presenting as autoimmune diseases: IPEX and APECED. J Clin Immunol. 2008;28 Suppl 1:S11–9.PubMedCrossRefGoogle Scholar
  15. 15.
    • Glocker EO, Kotlarz D, Boztug K, Gertz EM, Schäffer AA, Noyan F, et al. Inflammatory bowel disease and mutations affecting the Interleukin-10 Receptor. N Engl J Med. 2009;361:2033–45. First report on IL10R deficient patients and therapy by HSCT.PubMedCrossRefGoogle Scholar
  16. 16.
    • Glocker EO, Frede N, Perro M, Sebire N, Elawad M, Shah N, et al. Infant colitis – it’s in the genes. Lancet. 2010;376:1272. First report on patients with early-onset IBD and mutant IL-10.PubMedCrossRefGoogle Scholar
  17. 17.
    • Begue B, Verdier J, Rieux-Laucat F, Goulet O, Morali A, Canioni D, et al. Defective IL-10 signaling defining a subgroup of patients with inflammatory bowel disease. Am J Gastroenterol. 2011;106:1544–55. Demonstrates impaired IL22 signaling in intestinal tissue samples of a patient with IL10R2 deficiency.PubMedCrossRefGoogle Scholar
  18. 18.
    • Kotlarz D, Beier R, Murugan D, Diestelhorst J, Jensen O, Boztug K, et al. Loss of interleukin-10 signaling and infantile inflammatory bowel disease - implications for diagnosis and therapy. Gastroenterology. 2012;143:347–55. Most recent study on IL-10/IL10R deficiency and curative therapy using HSCT. Google Scholar
  19. 19.
    • Moran CJ, Walters TD, Guo CH, Kugathasan S, Klein C, Turner D, et al. IL10R polymorphisms are associated with very-early-onset ulcerative colitis. Inflamm Bowel Dis. 2012. doi:10.1002/ibd.22974. First identification of a splice site mutation in IL10R1 resulting in infantile onset IBD.
  20. 20.
    • Mao H, Yang W, Lee PP, Ho MH, Yang J, Zeng S, et al. Exome sequencing identifies novel compound heterozygous mutations of IL-10 receptor 1 in neonatal-onset Crohn's disease. Genes Immun. 2012;13:437–42. First description of a compound heterozygous mutation causing IL10R deficiency and IBD.Google Scholar
  21. 21.
    • Blaydon DC, Biancheri P, Di WL, Plagnol V, Cabral RM, Brooke MA, et al. Inflammatory skin and bowel disease linked to ADAM17 deletion. N Engl J Med. 2011;365:1502–8. Most recent genetic defect associated with IBD and skin disease.PubMedCrossRefGoogle Scholar
  22. 22.
    Gatti RA, Meuwissen HJ, Allen HD, Hong R, Good RA. Immunological reconstitution of sex-linked lymphopenic immunological deficiency. Lancet. 1968;2:1366–9.PubMedCrossRefGoogle Scholar
  23. 23.
    Gennery AR, Slatter MA, Grandin L, Taupin P, Cant AJ, Veys P, et al. Inborn errors working party of the European group for blood and marrow transplantation; european society for immunodeficiency. Transplantation of hematopoietic stem cells and long-term survival for primary immunodeficiencies in Europe: entering a new century, do we do better? J Allergy Clin Immunol. 2010;126:602–10.PubMedCrossRefGoogle Scholar
  24. 24.
    Thapar N, Shah N, Ramsay AD, Lindley KJ, Milla PJ. Long-term outcome of intractable ulcerating enterocolitis of infancy. J Pediatr Gastroenterol Nutr. 2005;40:582–8.PubMedCrossRefGoogle Scholar
  25. 25.
    Bogdan C, Vodovotz Y, Nathan C. Macrophage deactivation by interleukin 10. J Exp Med. 1991;174:1549–55.PubMedCrossRefGoogle Scholar
  26. 26.
    Spencer SD, Di Marco F, Hooley J, Pitts-Meek S, Bauer M, Ryan AM, et al. The orphan receptor CRF2-4 is an essential subunit of the interleukin 10 receptor. J Exp Med. 1998;187:571–8.PubMedCrossRefGoogle Scholar
  27. 27.
    Kühn R, Löhler J, Rennick D, Rajewsky K, Müller W. Interleukin-10-deficient mice develop chronic enterocolitis. Cell. 1993;75:263–74.PubMedCrossRefGoogle Scholar
  28. 28.
    Berg DJ, Kühn R, Rajewsky K, Müller W, Menon S, Davidson N, et al. Interleukin-10 is a central regulator of the response to LPS in murine models of endotoxic shock and the Shwartzman reaction but not endotoxin tolerance. J Clin Invest. 1995;96:2339–47.PubMedCrossRefGoogle Scholar
  29. 29.
    Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003;4:330–6.PubMedCrossRefGoogle Scholar
  30. 30.
    Barnes M, Powrie F. Regulatory T cells reinforce intestinal homeostasis. Immunity. 2009;31:401–11.PubMedCrossRefGoogle Scholar
  31. 31.
    Gambineri E, Torgerson TR, Ochs HD. Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused by mutations of FOXP3, a critical regulator of T-cell homeostasis. Curr Opin Rheumatol. 2003;15:430–5.PubMedCrossRefGoogle Scholar
  32. 32.
    Franke A, Balschun T, Karlsen TH, Sventoraityte J, Nikolaus S, Mayr G, et al. Sequence variants in IL-10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat Genet. 2008;40:1319–23.PubMedCrossRefGoogle Scholar
  33. 33.
    Amre DK, Mack DR, Morgan K, Israel D, Lambrette P, Costea I, et al. Interleukin 10 (IL-10) gene variants and susceptibility for paediatric onset Crohn's disease. Aliment Pharmacol Ther. 2009;29:1025–31.PubMedCrossRefGoogle Scholar
  34. 34.
    Noguchi E, Homma Y, Kang X, Netea MG, Ma X. A Crohn's disease-associated NOD2 mutation suppresses transcription of human IL-10 by inhibiting activity of the nuclear ribonucleoprotein hnRNP-A1. Nat Immunol. 2009;10:471–9.PubMedCrossRefGoogle Scholar
  35. 35.
    Commins S, Steinke JW, Borish L. The extended IL-10 superfamily: IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, IL-28, and IL-29. J Allergy Clin Immunol. 2008;121:1108–11.PubMedCrossRefGoogle Scholar
  36. 36.
    Wolk K, Sabat R. Interleukin-22: a novel T- and NK-cell derived cytokine that regulates the biology of tissue cells. Cytokine Growth Factor Rev. 2006;17:367–80.PubMedCrossRefGoogle Scholar
  37. 37.
    Donnelly RP, Sheikh F, Kotenko SV, Dickensheets H. The expanded family of class II cytokines that share the IL-10 receptor-2(IL10R2) chain. J Leukoc Biol. 2004;76:314–21.PubMedCrossRefGoogle Scholar
  38. 38.
    Wolk K, Kunz S, Witte E, Friedrich M, Asadullah K, Sabat R. IL-22 increases the innate immunity of tissues. Immunity. 2004;21:241–54.PubMedCrossRefGoogle Scholar
  39. 39.
    Wolk K, Witte E, Wallace E, Döcke WD, Kunz S, Asadullah K, et al. IL-22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential role in psoriasis. Eur J Immunol. 2006;36:1309–23.PubMedCrossRefGoogle Scholar
  40. 40.
    Sugimoto K, Ogawa A, Mizoguchi E, Shimomura Y, Andoh A, Bhan AK, et al. IL-22 ameliorates intestinal inflammation in a mouse model of ulcerative colitis. J Clin Invest. 2008;118:534–44.PubMedGoogle Scholar
  41. 41.
    Zenewicz LA, Yancopoulos GD, Valenzuela DM, Murphy AJ, Stevens S, Flavell RA. Innate and adaptive interleukin-22 protects mice from inflammatory bowel disease. Immunity. 2008;29:947–57.PubMedCrossRefGoogle Scholar
  42. 42.
    Zheng Y, Valdez PA, Danilenko DM, Hu Y, Sa SM, Gong Q, et al. Interleukin-22 mediates early host defense against attaching and effacing bacterial pathogens. Nat Med. 2008;14:282–9.PubMedCrossRefGoogle Scholar
  43. 43.
    Aujla SJ, Chan YR, Zheng M, Fei M, Askew DJ, Pociask DA, et al. IL-22 mediates mucosal host defense against gram-negative bacterial pneumonia. Nat Med. 2008;14:275–81.PubMedCrossRefGoogle Scholar
  44. 44.
    Kotenko SV, Gallagher G, Baurin VV, Lewis-Antes A, Shen M, Shah NK, et al. IFN-λs mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol. 2003;4:69–77.PubMedCrossRefGoogle Scholar
  45. 45.
    Sheppard P, Kindsvogel W, Xu W, Henderson K, Schlutsmeyer S, Whitmore TE, et al. IL-28, IL-29 and their class II cytokine receptor IL-28R. Nat Immunol. 2003;4:63–8.PubMedCrossRefGoogle Scholar
  46. 46.
    Moore KW, de Waal Malefyt R, Coffman RL, O'Garra A. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol. 2001;19:683–765.PubMedCrossRefGoogle Scholar
  47. 47.
    Schreiber S, Heinig T, Thiele HG, Raedler A. Immunoregulatory role of interleukin 10 in patients with inflammatory bowel disease. Gastroenterology. 1995;108:1434–44.PubMedCrossRefGoogle Scholar
  48. 48.
    Schreiber S, Fedorak RN, Nielsen OH, Wild G, Williams CN, Nikolaus S, et al. Safety and efficacy of recombinant human interleukin 10 in chronic active Crohn's disease. Crohn's Disease IL-10 Cooperative Study Group. Gastroenterology. 2000;119:1461–72.PubMedCrossRefGoogle Scholar
  49. 49.
    Fedorak RN, Gangl A, Elson CO, Rutgeerts P, Schreiber S, Wild G, 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;119:1473–82.PubMedCrossRefGoogle Scholar
  50. 50.
    Tilg H, van Montfrans C, van den Ende A, Kaser A, van Deventer SJ, Schreiber S, et al. Treatment of Crohn's disease with recombinant human interleukin 10 induces the proinflammatory cytokine interferon gamma. Gut. 2002;50:191–5.PubMedCrossRefGoogle Scholar
  51. 51.
    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;113:383–9.PubMedCrossRefGoogle Scholar
  52. 52.
    Steidler L, Hans W, Schotte L, Neirynck S, Obermeier F, Falk W, et al. Treatment of murine colitis by Lactococcus lactis secreting interleukin-10. Science. 2000;289:1352–5.PubMedCrossRefGoogle Scholar
  53. 53.
    Braat H, Rottiers P, Hommes DW, Huyghebaert N, Remaut E, Remon JP, et al. A phase I trial with transgenic bacteria expressing interleukin-10 in Crohn's disease. Clin Gastroenterol Hepatol. 2006;4:754–9.PubMedCrossRefGoogle Scholar
  54. 54.
    Nakase H, Okazaki K, Tabata Y, Ozeki M, Watanabe N, Ohana M, et al. New cytokine delivery system using gelatin microspheres containing interleukin-10 for experimental inflammatory bowel disease. J Pharmacol Exp Ther. 2002;301:59–65.PubMedCrossRefGoogle Scholar
  55. 55.
    Lindsay JO, Ciesielski CJ, Scheinin T, Brennan FM, Hodgson HJ. Local delivery of adenoviral vectors encoding murine interleukin 10 induces colonic interleukin 10 production and is therapeutic for murine colitis. Gut. 2003;52:981–7.PubMedCrossRefGoogle Scholar
  56. 56.
    Barbara G, Xing Z, Hogaboam CM, Gauldie J, Collins SM. Interleukin 10 gene transfer prevents experimental colitis in rats. Gut. 2000;46:344–9.PubMedCrossRefGoogle Scholar
  57. 57.
    Bhavsar MD, Amiji MM. Oral IL-10 gene delivery in a microsphere-based formulation for local transfection and therapeutic efficacy in inflammatory bowel disease. Gene Ther. 2008;15:1200–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Van Montfrans C, Rodriguez Pena MS, Pronk I, Ten Kate FJ, Te Te Velde AA, Van Deventer SJ. Prevention of colitis by interleukin 10-transduced T lymphocytes in the SCID mice transfer model. Gastroenterology. 2002;123:1865–76.PubMedCrossRefGoogle Scholar
  59. 59.
    McCarthy BA, Reddi AS, Coakley KM, Nguyen SM, Nayal RR, Javdan M, et al. Administration of human umbilical cord blood cells produces interleukin-10 (IL-10) in IL-10 deficient mice without immunosuppression. Curr Stem Cell Res Ther. 2010;5:13–6.PubMedCrossRefGoogle Scholar
  60. 60.
    Bamba S, Lee CY, Brittan M, Preston SL, Direkze NC, Poulsom R, et al. Bone marrow transplantation ameliorates pathology in interleukin-10 knockout colitic mice. J Pathol. 2006;209:265–73.PubMedCrossRefGoogle Scholar
  61. 61.
    Donnelly RP, Dickensheets H, Finbloom DS. The interleukin-10 signal transduction pathway and regulation of gene expression in mononuclear phagocytes. J Interferon Cytokine Res. 1999;19:563–73.PubMedCrossRefGoogle Scholar
  62. 62.
    Murray PJ. The JAK-STAT signaling pathway: input and output integration. J Immunol. 2007;178:2623–9.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Neil Shah
    • 1
  • Jochen Kammermeier
    • 1
  • Mamoun Elawad
    • 1
  • Erik-Oliver Glocker
    • 2
  1. 1.Department of Paediatric GastroenterologyGreat Ormond Street Hospital, University College LondonLondonUK
  2. 2.Institute of Medical Microbiology and HygieneUniversity Hospital FreiburgFreiburgGermany

Personalised recommendations