Genetic predisposition is a risk factor for the development of inflammatory bowel diseases (IBDs). Disruption of the interleukin (IL)-10 pathway in mice causes intestinal inflammation similar to human IBD. Two common non-synonymous IL-10R1 variants, S138G and G330R, were cloned and expressed in HeLa and Ba/F3. A reduction in IL-10-induced STAT1 and STAT3 activation was seen for IL-10R1-S138G (but not IL-10R1-G330R) by phosphospecific western blotting in both cell types. When analyzing 52 world populations for the presence of IL-10R1 variants, a strong dissimilarity was found between major geographical regions. In addition, when 182 IBD–parent trios were genotyped for both variants, a reduced transmission of haplotype -7 (carrying the S138G variant allele) to offspring with ulcerative colitis (UC) was observed. This UC-protective effect of S138G was confirmed in a Hungarian cohort (n=185, allele frequency 11.6 versus 17.5%; P=0.017) but not in an independent Belgian cohort (n=666, allele frequency 15.9 versus 15.5%; P=0.8). In conclusion, the IL-10R1 S138G variant is a loss-of-function allele for IL-10-induced STAT1 and STAT3 activation but does not protect from UC susceptibility.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Genes & Immunity Open Access 09 June 2011
Subscribe to Journal
Get full journal access for 1 year
only $14.88 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Hampe J, Cuthbert A, Croucher PJ, Mirza MM, Mascheretti S, Fisher S et al. Association between insertion mutation in NOD2 gene and Crohn's disease in German and British populations. Lancet 2001; 357: 1925–1928.
Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease. Nature 2001; 411: 599–603.
Ogura Y, Bonen DK, Inohara N, Nicolae DL, Chen FF, Ramos R et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature 2001; 411: 603–606.
Gasche C, Alizadeh BZ, Pena AS . Genotype–phenotype correlations: how many disorders constitute inflammatory bowel disease? Eur J Gastroenterol Hepatol 2003; 15: 599–606.
Barrett JC, Hansoul S, Nicolae DL, Cho JH, Duerr RH, Rioux JD et al. Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease. Nat Genet 2008; 40: 955–962.
Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ et al. A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 2006; 314: 1461–1463.
Pestka S, Krause CD, Sarkar D, Walter MR, Shi Y, Fisher PB . Interleukin-10 and related cytokines and receptors. Annu Rev Immunol 2004; 22: 929–979.
Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W . Interleukin-10-deficient mice develop chronic enterocolitis. Cell 1993; 75: 263–274.
Rennick DM, Fort MM, Davidson NJ . Studies with IL-10-/- mice: an overview. J Leukoc Biol 1997; 61: 389–396.
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: 571–578.
Takeda K, Clausen BE, Kaisho T, Tsujimura T, Terada N, Forster I et al. Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 1999; 10: 39–49.
Autschbach F, Braunstein J, Helmke B, Zuna I, Schurmann G, Niemir ZI et al. In situ expression of interleukin-10 in noninflamed human gut and in inflammatory bowel disease. Am J Pathol 1998; 153: 121–130.
Gasche C, Bakos S, Dejaco C, Tillinger W, Zakeri S, Reinisch W . IL-10 secretion and sensitivity in normal human intestine and inflammatory bowel disease. J Clin Immunol 2000; 20: 362–370.
Ho AS, Liu Y, Khan TA, Hsu DH, Bazan JF, Moore KW . A receptor for interleukin 10 is related to interferon receptors. Proc Natl Acad Sci USA 1993; 90: 11267–11271.
Kotenko SV, Krause CD, Izotova LS, Pollack BP, Wu W, Pestka S . Identification and functional characterization of a second chain of the interleukin-10 receptor complex. EMBO J 1997; 16: 5894–5903.
Kotenko SV, Langer JA . Full house: 12 receptors for 27 cytokines. Int Immunopharmacol 2004; 4: 593–608.
Finbloom DS, Winestock KD . IL-10 induces the tyrosine phosphorylation of tyk2 and Jak1 and the differential assembly of STAT1 alpha and STAT3 complexes in human T cells and monocytes. J Immunol 1995; 155: 1079–1090.
Stahl N, Farruggella TJ, Boulton TG, Zhong Z, Darnell Jr JE, Yancopoulos GD . Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors. Science 1995; 267: 1349–1353.
Darnell Jr JE . STATs and gene regulation. Science 1997; 277: 1630–1635.
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: 563–573.
Riley JK, Takeda K, Akira S, Schreiber RD . Interleukin-10 receptor signaling through the JAK–STAT pathway. Requirement for two distinct receptor-derived signals for anti-inflammatory action. J Biol Chem 1999; 274: 16513–16521.
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: 383–389.
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. Gastroenterology 2000; 119: 1473–1482.
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. Gastroenterology 2000; 119: 1461–1472.
Gasche C, Grundtner P, Zwirn P, Reinisch W, Shaw SH, Zdanov A et al. Novel variants of the IL-10 receptor 1 affect inhibition of monocyte TNF-alpha production. J Immunol 2003; 170: 5578–5582.
Wirtz S, Finotto S, Kanzler S, Lohse AW, Blessing M, Lehr HA et al. Chronic intestinal inflammation in STAT-4 transgenic mice: characterization of disease and adoptive transfer by TNF- plus IFN-gamma-producing CD4+ T cells that respond to bacterial antigens. J Immunol 1999; 162: 1884–1888.
Cavalli-Sforza LL, Feldman MW . The application of molecular genetic approaches to the study of human evolution. Nat Genet 2003; 33 (Suppl): 266–275.
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: 754–759.
Gasche C, Scholmerich J, Brynskov J, D'Haens G, Hanauer SB, Irvine EJ et al. A simple classification of Crohn's disease: report of the Working Party for the World Congresses of Gastroenterology, Vienna 1998. Inflamm Bowel Dis 2000; 6: 8–15.
Rosenberg NA, Pritchard JK, Weber JL, Cann HM, Kidd KK, Zhivotovsky LA et al. Genetic structure of human populations. Science 2002; 298: 2381–2385.
Cann HM, de Toma C, Cazes L, Legrand MF, Morel V, Piouffre L et al. A human genome diversity cell line panel. Science 2002; 296: 261b–262b.
Terwilliger JD, Ott J . Handbook of Human Genetic Linkage. Johns Hopkins University Press: Baltimore, Maryland, 1994, pp 188–193.
Markianos K, Daly MJ, Kruglyak L . Efficient multipoint linkage analysis through reduction of inheritance space. Am J Hum Genet 2001; 68: 963–977.
We are grateful to Dr Rainer de Martin (Medical University of Vienna) for inspiring advice and Birgit Rapp, Verena Kratzer and Manuela Nemeth for excellent technical assistance and to the Foundation Jean Dausset (CEPH) for providing the DNA samples. The study has been supported by the Austrian Science Fund (P15314 and P17943 to CG) and the OeNB Anniversary Fund (ONB10543 to CG).
About this article
Cite this article
Grundtner, P., Gruber, S., Murray, S. et al. The IL-10R1 S138G loss-of-function allele and ulcerative colitis. Genes Immun 10, 84–92 (2009). https://doi.org/10.1038/gene.2008.72
- inflammatory bowel disease
- ulcerative colitis
- interleukin-10 receptor
- single-nucleotide polymorphism
This article is cited by
Association between polymorphisms in the promoter region of interleukin-10 and susceptibility to inflammatory bowel disease
Molecular Biology Reports (2014)
Exome sequencing identifies novel compound heterozygous mutations of IL-10 receptor 1 in neonatal-onset Crohn's disease
Genes & Immunity (2012)
Genes & Immunity (2011)