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Differential regulation of interleukin-10 production by genetic and environmental factors – a twin study

Genes & Immunity volume 3, pages 407–413 (2002)Cite this article

Abstract

Interleukin-10 (IL-10) has a critical role in the regulation of immune responses. The relative contribution of genetic and environmental factors to IL-10 production is under debate. We performed a twin study in 246 monozygotic and dizygotic twins to assess the heritability of IL-10 production after LPS stimulation in whole blood. In addition, the influence of promoter single nucleotide polymorphisms (−1082, −819 and −592) on transcriptional activity and their binding to nuclear factors was studied in luciferase reporter gene and electrophoretic mobility shift assays. IL-10 production showed a genetic determination with a heritability of 0.5. Decreasing body mass index (BMI), smoking and female gender lead to decreased IL-10 production. In monocytes, the −1082A allele showed higher binding affinity to the transcription factor PU.1 resulting in decreased transcriptional activity of −1082A promoter haplotypes. Genetic determination of IL-10 secretion is probably lower than that previously reported. Fifty percent of the observed variability explained by genetic factors. Female individuals produce less IL-10 than male subjects. Environmental factors like smoking and decreasing BMI exert suppressing effects on IL-10 production. Although the −1082A allele shows higher binding affinity to the PU.1 transcription factor and lower transcriptional activity, this polymorphism probably explains only a small fraction of the observed heritability.

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References

  1. Mosmann TR . Properties and functions of interleukin-10 Adv Immunol 1994 56: 1–26

    Article  CAS  PubMed  Google Scholar 

  2. Fiorentino DF, Zlotnik A, Mosmann TR, Howard M, O'Garra A . IL-10 inhibits cytokine production by activated macrophages J Immunol 1991 147: 3815–3822

    CAS  PubMed  Google Scholar 

  3. Wanidworanun C, Strober W . Predominant role of tumor necrosis factor-alpha in human monocyte IL-10 synthesis J Immunol 1993 151: 6853–6861

    CAS  PubMed  Google Scholar 

  4. Rousset F, Garcia E, Defrance T et al. Interleukin 10 is a potent growth and differentiation factor for activated human B lymphocytes Proc Natl Acad Sci USA 1992 89: 1890–1893

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Llorente L, Zou W, Levy Y et al. Role of interleukin 10 in the B lymphocyte hyperactivity and autoantibody production of human systemic lupus erythematosus J Exp Med 1995 181: 839–844

    Article  CAS  PubMed  Google Scholar 

  6. Murray PJ, Wang L, Onufryk C, Tepper RI, Young RA . T cell-derived IL-10 antagonizes macrophage function in mycobacterial infection J Immunol 1997 158: 315–321

    CAS  PubMed  Google Scholar 

  7. Derkx B, Marchant A, Goldman M, Bijlmer R, van Deventer S . High levels of interleukin-10 during the initial phase of fulminant meningococcal septic shock J Infect Dis 1995 171: 229–232

    Article  CAS  PubMed  Google Scholar 

  8. van Furth AM, Seijmonsbergen EM, Langermans JA, Groeneveld PH, de Bel CE, van Furth R . High levels of interleukin 10 and tumor necrosis factor alpha in cerebrospinal fluid during the onset of bacterial meningitis Clin Infect Dis 1995 21: 220–222

    Article  CAS  PubMed  Google Scholar 

  9. Burdin N, Rousset F, Banchereau J . B-cell-derived IL-10: production and function Methods 1997 11: 98–111

    Article  CAS  PubMed  Google Scholar 

  10. Bienvenu J, Doche C, Gutowski MC, Lenoble M, Lepape A, Perdrix JP . Production of proinflammatory cytokines and cytokines involved in the TH1/TH2 balance is modulated by pentoxifylline J Cardiovasc Pharmacol 1995 25: (Suppl 2) S80-S84

    Google Scholar 

  11. Westendorp RG, Langermans JA, Huizinga TW, Verweij CL, Sturk A . Genetic influence on cytokine production in meningococcal disease Lancet 1997 349: 1912–1913

    Article  CAS  PubMed  Google Scholar 

  12. Eskdale J, Gallagher G . A polymorphic dinucleotide repeat in the human IL-10 promoter Immunogenetics 1995 42: 444–445

    Article  CAS  PubMed  Google Scholar 

  13. Eskdale J, Kube D, Gallagher G . A second polymorphic dinucleotide repeat in the 5' flanking region of the human IL10 gene Immunogenetics 1996 45: 82–83

    Article  CAS  PubMed  Google Scholar 

  14. Turner DM, Williams DM, Sankaran D, Lazarus M, Sinnott PJ, Hutchinson IV . An investigation of polymorphism in the interleukin-10 gene promoter Eur J Immunogenet 1997 24: 1–8

    Article  CAS  PubMed  Google Scholar 

  15. Eskdale J, Gallagher G, Verweij CL, Keijsers V, Westendorp RG, Huizinga TW . Interleukin 10 secretion in relation to human IL-10 locus haplotypes Proc Natl Acad Sci USA 1998 95: 9465–9470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Bidwell J, Keen L, Gallagher G et al. Cytokine gene polymorphism in human disease: on-line databases Genes Immun 1999 1: 3–19

    Article  CAS  PubMed  Google Scholar 

  17. Crawley E, Kay R, Sillibourne J, Patel P, Hutchinson I, Woo P . Polymorphic haplotypes of the interleukin-10 5' flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis Arthritis Rheum 1999 42: 1101–1108

    Article  CAS  PubMed  Google Scholar 

  18. Nieters A, Brems S, Becker N . Cross-sectional study on cytokine polymorphisms, cytokine production after T-cell stimulation and clinical parameters in a random sample of a German population Hum Genet 2001 108: 241–248

    Article  CAS  PubMed  Google Scholar 

  19. van der Linden MW, Huizinga TW, Stoeken DJ, Sturk A, Westendorp RG . Determination of tumour necrosis factor-alpha and interleukin-10 production in a whole blood stimulation system: assessment of laboratory error and individual variation J Immunol Methods 1998 218: 63–71

    Article  CAS  PubMed  Google Scholar 

  20. Kube D, Platzer C, von Knethen A et al. Isolation of the human interleukin 10 promoter. Characterization of the promoter activity in Burkitt's lymphoma cell lines Cytokine 1995 7: 1–7

    Article  CAS  PubMed  Google Scholar 

  21. Grainger DJ, Heathcote K, Chiano M et al. Genetic control of the circulating concentration of transforming growth factor type beta1 Hum Mol Genet 1999 8: 93–97

    Article  CAS  PubMed  Google Scholar 

  22. Takanashi S, Hasegawa Y, Kanehira Y et al. Interleukin-10 level in sputum is reduced in bronchial asthma, COPD and in smokers Eur Respir J 1999 14: 309–314

    Article  CAS  PubMed  Google Scholar 

  23. Rioux N, Castonguay A . 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone modulation of cytokine release in U937 human macrophages Cancer Immunol Immunother 2001 49: 663–670

    Article  CAS  PubMed  Google Scholar 

  24. Crepieux P, Coll J, Stehelin D . The Ets family of proteins: weak modulators of gene expression in quest for transcriptional partners Crit Rev Oncog 1994 5: 615–638

    CAS  PubMed  Google Scholar 

  25. Toda Y, Tsukada J, Misago M, Kominato Y, Auron PE, Tanaka Y . Autocrine induction of the human pro-IL-1beta gene promoter by IL-1beta in monocytes J Immunol 2002 168: 1984–1991

    Article  CAS  PubMed  Google Scholar 

  26. Borras FE, Lloberas J, Maki RA, Celada A . Repression of I-A beta gene expression by the transcription factor PU.1 J Biol Chem 1995 270: 24385–24391

    Article  CAS  PubMed  Google Scholar 

  27. Harendza S, Lovett DH, Stahl RA . The hematopoietic transcription factor PU.1 represses gelatinase A transcription in glomerular mesangial cells J Biol Chem 2000 275: 19552–19559

    Article  CAS  PubMed  Google Scholar 

  28. Zhang P, Behre G, Pan J et al. Negative cross-talk between hematopoietic regulators: GATA proteins repress PU.1 Proc Natl Acad Sci USA 1999 96: 8705–8710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Eskdale J, Keijsers V, Huizinga T, Gallagher G . Microsatellite alleles and single nucleotide polymorphisms (SNP) combine to form four major haplotype families at the human interleukin- 10 (IL-10) locus Genes Immun 1999 1: 151–155

    Article  CAS  PubMed  Google Scholar 

  30. D'Alfonso S, Rampi M, Rolando V, Giordano M, Momigliano-Richiardi P . New polymorphisms in the IL-10 promoter region Genes Immun 2000 1: 231–233

    Article  CAS  PubMed  Google Scholar 

  31. Gibson AW, Edberg JC, Wu J, Westendorp RG, Huizinga TW, Kimberly RP . Novel single nucleotide polymorphisms in the distal IL-10 promoter affect IL-10 production and enhance the risk of systemic lupus erythematosus J Immunol 2001 166: 3915–3922

    Article  CAS  PubMed  Google Scholar 

  32. Eskdale J, Wordsworth P, Bowman S, Field M, Gallagher G . Association between polymorphisms at the human IL-10 locus and systemic lupus erythematosus Tissue Antigens 1997 49: 635–639

    Article  CAS  PubMed  Google Scholar 

  33. Edwards-Smith CJ, Jonsson JR, Purdie DM, Bansal A, Shorthouse C, Powell EE . Interleukin-10 promoter polymorphism predicts initial response of chronic hepatitis C to interferon alfa Hepatology 1999 30: 526–530

    Article  CAS  PubMed  Google Scholar 

  34. Kaluza W, Leirisalo-Repo M, Marker-Hermann E et al. IL10.G microsatellites mark promoter haplotypes associated with protection against the development of reactive arthritis in Finnish patients Arthritis Rheum 2001 44: 1209–1214

    Article  CAS  PubMed  Google Scholar 

  35. Vogel F, Motulsky A . Human Genetics. Problems and Approaches 3rd completely revised edn Springer: Berlin 1997

    Book  Google Scholar 

  36. Inc. SI. SAS/STAT Software: Changes and Enhancements through Release 6.12 SAS Institute Inc 1997

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Acknowledgements

We thank Petra Adams, Anke Förgg, Annette Shresta, Beate Stradmann-Bellinghausen, and Jutta Lummer for their expert technical assistance. In addition, we are indebted to Evi Dietrich, Nina Evers, Stefan Wüst and Mohammed Aydi, who helped with patient recruitment.

Dr Thomas Höhler and Prof. Christian Rittner hold a grant by the Deutsche Forschungsgemeinschaft, SFB 490, Project A3.

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Authors and Affiliations

  1. Department of Internal Medicine, Johannes Gutenberg-University, Mainz, Germany

    E Reuss, C Becker & T Höhler

  2. Institute for Medical Biometry, Informatics and Epidemiology, Rheinische Friedrichs Wilhelm University, Bonn, Germany

    R Fimmers

  3. Institute of Legal Medicine, Johannes Gutenberg-University Mainz, Germany

    A Kruger & C Rittner

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  1. E Reuss
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Correspondence to T Höhler.

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Reuss, E., Fimmers, R., Kruger, A. et al. Differential regulation of interleukin-10 production by genetic and environmental factors – a twin study. Genes Immun 3, 407–413 (2002). https://doi.org/10.1038/sj.gene.6363920

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