Association of the -1082 G/A polymorphism in the IL-10 gene promoter with production of autoantibodies in rheumatoid arthritis

Authors: P. Němec 1;  M. Goldbergová-Pávková 2;  J. Gatterová 3;  Z. Fojtík 4;  A. Vašků 2;  M. Souček 1
Authors‘ workplace: Revmatologická ambulance, II. interní klinika, Fakultní nemocnice u sv. Anny v Brně a Lékařské fakulty Masarykovy univerzity, Brno, 2Ústav patologické fyziologie, Lékařské fakulty Masarykovy univerzity, Brno 1;  Revmatologický ústav, Praha, 4Revmatologická ambulance, Interní a hematoonkologická klinika Fakultní nemocnice Brno a Lékařské fakulty Masarykovy univerzity, Brno 3
Published in: Čes. Revmatol., 16, 2008, No. 3, p. 104-109.
Category: Original Papers


Interleukin-10 (IL-10) is an immunoregulatory cytokine, usually considered to mediate downregulation of the inflammatory response in rheumatoid arthritis (RA). Some effects of IL-10 are not anti-inflammatory, for example activation of B cells to promote autoantibody production. Allelic polymorphisms located in the promoter region of IL-10 gene may contribute to the regulation of autoantibodies production. To examine the association between both individual IL-10 single nucleotide polymorphism -1082 G/A with the production of rheumatoid factors (RFs) in RA patients. A total of 151 patients with RA diagnosed according to the revised criteria of the American College of Rheumatology for RA were consecutively recruited into the study. All patients had a disease duration from the first manifestation of the disease symptoms of at least 24 months. Polymerase chain reaction amplification was used for analysis of the promoter polymorphism of the IL-10 gene. Serum levels of RFs were measured by ELISA. We observed significant differences in genotype distribution of the -1082 G/A polymorphism between IgM RF, IgA RF, and IgG RF positive/negative subgroups of RA patients, with higher prevalence of the GG genotype within IgM RF (Pg = 0.006), IgA RF (Pg = 0.05), and IgG RF (Pg = 0.007) negative RA patients. Results obtained in this study provide the evidence of an association of the -1082 G/A polymorphism in IL-10 gene promoter with the production of RFs, which are associated with poorer prognosis of RA.

Key words:
autoantibody, gene, interleukin-10, polymorphism, rheumatoid arthritis, rheumatoid factor


1. Reveille JD. The genetic contribution to the pathogenesis of rheumatoid arthritis. Curr Opin Rheumatol 1998; 10 (3): 187–200.

2. Winchester R. The molecular basis of susceptibility to rheumatoid arthritis. Adv Immunol 1994; 56: 389–466.

3. Singal DP, Li J, Lei K. Genetics of rheumatoid arthritis (RA): two separate regions in the major histocompatibility complex contribute to susceptibility to RA. Immunol Lett 1999; 69 (3): 301–6.

4. Rowley MJ, Stockman A, Brand CA, Tait BD, Rowley GL, Sherritt MA, et al. The effect of HLA-DRB1 disease susceptibility markers on the expression of RA. Scand J Rheumatol 1997; 26 (6): 448–55.

5. Joyce DA, Gibbons DP, Green P, Steer JH, Feldmann M, Brennan FM. Two inhibitors of pro-inflammatory cytokine release, interleukin-10 and interleukin-4, have contrasting effects on release of soluble p75 tumor necrosis factor receptor by cultured monocytes. Eur J Immunol 1994; 24 (11): 2699–705.

6. Hart PH, Ahern MJ, Smith MD, Finlayjones JJ. Regulatory effects of IL-13 on synovial fluid macrophages and blood monocytes from patients with inflammatory arthritis. Clin Exp Immunol 1995; 99 (3): 331–7.

7. Kawakami A, Eguchi K, Matsuoka N, Tsuboi M, Urayama S, Kawabe Y, et al. Inhibitory effects of interleukin-10 on synovial cells of rheumatoid arthritis. Imunology 1997; 91 (2): 252–9.

8. Brennan FM. IL-10 and arthritis. Rheumatology 1999; 38 (4): 293–7.

9. Westendorp RG, Langermans JA, Huizinga TW, Elouali AH, Verweij CL, Boomsma DI, et al. Genetic influence on cytokine production and fatal meningococcal disease. Lancet 1997; 349 (9046): 170–3.

10. Pretolani M, Goldman M. IL-10. A potential therapy for allergic inflammation? Immunol Today 1997; 18 (6): 277–80.

11. Perez L, Orte J, Brieva JA. Terminal differentiation of spontaneous rheumatoid factor-secreting B-cells from rheumatoid arthritis patients depends on endogenous interleukin-10. Arthritis Rheum 1995; 38 (12): 1771–6.

12. Cush JJ, Splawski JB, Thomas R, McFarlin JE, Schulze-Koops H, Davis LS, et al. Elevated interleukin-10 levels in patients with rheumatoid arthritis. Arthritis Rheum 1995; 38 (1): 96–104.

13. Eskdale J, Kube D, Tesch H, Gallagher G. Mapping of the human IL10 gene and further characterization of the 5’ flanking sequence. Immunogenetics 1997; 46 (2): 120–8.

14. Eskdale J, Gallagher G. A polymorphic dinucleotide repeat in the human IL-10 promoter. Immunogenetics 1995; 42 (5): 444–5.

15. Eskdale J, Kube D, Gallagher G.A second polymorphic dinucleotide repeat in the 5’ flanking region of the human IL10 gene. Immunogenetics 1996; 45 (1): 82–3.

16. Tumor necrosis factor locus polymorphisms in rheumatoid arthritis. Tissue Antigens 1997; 50 (3): 303–7.

17. 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 (2): 151–5.

18. D’Alfonso S, Rampi M, Rolando V, Giordano M, Momigliano-Richiardi P. New polymorphisms in the IL-10 promoter region. Genes Immun 2000; 1 (3): 213–33.

19. 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): 1–8.

20. 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 (6): 1101–8

21. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classiffication of rheumatoid arthritis. Arthritis Rheum 1988; 31 (3): 315-24.

22. Sharp JT, Young DY, Bluhm GB, Brook A, Brower AC, Corbett M, et al. How many joints in the hands and wrists should be included in a score of radiologic abnormalities used to assess rheumatoid arthritis. Arthritis Rheum 1985; 28 (12): 1326–35.

23. Matsuda M, Salazar F, Petersson M, Masucci G, Hansson J, Pisa P, et al. Interleukin 10 pretreatment protects target cells from tumor- and allo-specific cytotoxic T cells and downregulates HLA class I expression. J Exp Med 1994; 180 (6): 2371–6.

24. Rennick DM, Fort MM, Davidson NJ. Studies with IL-10(–/–) mice: An overview. J Leukoc Biol 1997; 61 (4): 389–96

25. Lacraz S, Nicod LP, Chicheportiche R, Welgus HG, Dayer JM. IL-10 inhibits metalloproteinase and stimulates TIMP-1 production in human mononuclear phagocytes. J Clin Invest 1995; 96 (5): 2304–10.

26. Persson S, Mikulowska A, Narula S, Ogarra A, Holmdahl R. Interleukin-10 suppresses the development of collagen type II-induced arthritis and ameliorates sustained arthritis in rats. Scand J Immunol 1996; 44 (6): 607–14.

27. Joosten LA, Lubberts E, Durez P, Helsen MM, Jacobs MJ, Goldman M, et al. Role of interleukin-4 and interleukin-10 in murine collagen-induced arthritis: Protective effect of interleukin-4 and interleukin-10 treatment on cartilage destruction. Arthritis Rheum 1997; 40 (2): 249–60.

28. Lubberts E, Joosten LAB, Helsen MMA, Vandenberg WB. Regulatory role of interleukin 10 in joint inflammation and cartilage destruction in murine streptococcal cell wall (SCW) arthritis. More therapeutic benefit with IL-4/IL-10 combination therapy than with IL-10 treatment alone. Cytokine 1998; 10 (5): 361–9.

29. Huang SC, Jiang R, Hufnagle WO, Furst DE, Wilske KR, Milner EC. V-H usage and somatic hypermutation in peripheral blood B cells of patients with rheumatoid arthritis (RA). Clin Exp Immunol 1998; 112 (3): 516–27.

30. Wanidworanun C, Strober W. Predominant role of tumor necrosis factor-alpha in human monocyte IL-10 synthesis. J Immunol 1993; 151 (12): 6853–61.

31. 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 U S A 1998; 95 (16): 9465–70.

32. Huizinga TW, Keijsers V, Yanni G, Hall M, Ramage W, Lanchbury J, et al. Are differences in interleukin 10 production associated with joint damage? Rheumatology (Oxford) 2000; 39 (11): 1180–8.

33. Rood MJ, Keijsers V, van der Linden MW, Tong TQ, Borggreve SE, Verweij CL, et al. Neuropsychiatric SLE is associated with imbalance in IL-10 promoter haplotypes. Ann Rheum Dis 1999; 58 (2): 85–9.

34. Hajeer AH, Lazarus M, Turner D, Mageed RA, Vencovsky J, Sinnott P, et al. IL-10 gene promoter polymorphisms in rheumatoid arthritis.Scand J Rheumatol 1998; 27 (2): 142–5.

35. Coakley G, Mok CC, Hajeer AH, Ollier WE, Turner D, Sinnott PJ, et al. IL-10 promoter polymorphisms in RA and Felty’s syndrome. Br J Rheumatol 1998; 37 (9): 988–91.

36. Martinez A, Pascual M, Pascual-Salcedo D, Balsa A, Martin J, de la Concha EG. Genetic polymorphisms in Spanish rheumatoid arthritis patients: an association and linkage study. Genes Immun 2003; 4 (2): 117–21.

37. Moreno OM, González CI, Saaibi DL, Otero W, Badillo R, Martín J, et al. Polymorphisms of IL-10 gene promoter and rheumatoid arthritis in a Colombian population. Biomedica 2007; 27 (1): 56–65.

38. Eguchi K. Early prediction of joint destruction in rheumatoid arthritis. Clin Calcium 2007; 17 (4): 517–25.

39. Johnson PM, Faulk WP. Rheumatoid factor: its nature, specificity, and production in rheumatoid arthritis. Clin Immunol Immunopathol 1976; 6 (3): 414–30.

40. van Zeben D, Breedveld FC. Prognostic factors in rheumatoid arthritis.J Rheumatol 1996; 44 (Suppl): 31–3.

41. Agrawal S, Misra R, Aggarwal A. Autoantibodies in rheumatoid arthritis: association with severity of disease in established RA. Clin Rheumatol 2007; 26 (2): 201–4.

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