Digestive Diseases and Sciences

, Volume 51, Issue 11, pp 2039–2044

Dopamine D2 Receptor Polymorphisms in Inflammatory Bowel Disease and the Refractory Response to Treatment

  • F. Magro
  • E. Cunha
  • F. Araujo
  • E. Meireles
  • P. Pereira
  • M. Dinis-Ribeiro
  • F. Tavarela Veloso
  • R. Medeiros
  • P. Soares-da-Silva
Original Paper

Abstract

Dopamine and its receptors may be involved in inflammatory reaction. The availability of this molecule depends on its receptors. The DRD2 gene, which codifies for the D2 dopamine receptor, has several polymorphisms. In this study, the DRD2 TaqIA polymorphism, which confers a decreased receptor density, was evaluated in 313 individuals including 220 inflammatory bowel disease patients (143 patients with Crohn’s disease and 77 with ulcerative colitis) and in 93 healthy blood donors. The analysis was carried out by PCR-RFLP techniques. The frequencies of A1A1 and A2A2 genotypes were similar among Crohn’s disease, ulcerative colitis patients, and health controls. Also, the genotype frequency was similar in different groups of disease localization, behavior, and age of disease onset. However, the Crohn’s disease patients carriers of A2A2 genotype showed a lower risk for development refractory Crohn’s disease (37 out 65) than A1A1 and A1A2 carriers (28 out of 65) [(OR=0.4, 95% CI 0.21–0.87; p=0.02)]. Our results support an involvement of the dopamine receptor in inflammatory bowel disease and suggest a new potential target for therapy in refractory Crohn’s disease patients.

Keywords

Inflammatory bowel disease Dopamine Crohn’s disease Polymorphism Refractory disease 

References

  1. 1.
    Groux H, Powrie F (1999) Regulatory T cells and inflammatory bowel disease. Immunol Today 20:442–445PubMedCrossRefGoogle Scholar
  2. 2.
    Strober W, Kelsall B, Fuss I, Marth T, Ludviksson B, Ehrhardt R, Neurath M (1997) Reciprocal IFN-gamma and TGF-beta responses regulate the occurrence of mucosal inflammation. Immunol Today 18:61–64PubMedCrossRefGoogle Scholar
  3. 3.
    Stangi J, Parkes M, Louis E (1996) Two stage genoma-with search in inflammatory bowel disease provides evidence for susceptibility loci on chromossoma 3,7 and 12. Nat Genet 14:199–202CrossRefGoogle Scholar
  4. 4.
    Hugot JP, Chamaillard M, Zouali H (2001) Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature 411:599–603PubMedCrossRefGoogle Scholar
  5. 5.
    Ogura Y, Bonen DK, Inohara N (2001) A frameshift mutation in NOD2 associated with susceptibility to Cohn’s disease. Nature 411:603–606PubMedCrossRefGoogle Scholar
  6. 6.
    Ader S, Felton D, Cohn N (1990) Interactions between the brain and the immune system. Annu Rev Pharmacol Toxicol 30:561–602PubMedCrossRefGoogle Scholar
  7. 7.
    Basu S, Dasgupta PS (2000) Dopamine, a neurotransmitter, influences the immune system. J Neuroimmunol 102:113–124PubMedCrossRefGoogle Scholar
  8. 8.
    McKenna F, Mclaughlin PJ, Lweis BJ, Sibbring GC, Cumerson JA, Bowen-Jones D (2002) Dopamine receptor expression on human T and B-lymphocytes, monocytes, neutrophils, eosinophils and NK cells: a flow cytometric study. J Neuroimmunol 132:34–40PubMedCrossRefGoogle Scholar
  9. 9.
    Ricci A, Vegilio F, Amenta F (1995) Radioligand binding characterization of putative dopamine D3 receptor in human peripheral blood lymphocytes with 3H-7-OH-DPAT. J Neuroimmunol 58:139–144PubMedCrossRefGoogle Scholar
  10. 10.
    Bergquist J, Tarkowski A, Ekman R, Ewing A (1994) Discovery of endogenous catecholamines in lymphocytes and evidence for catecholamines regulation of lymphocytes function via an autocrine loop. Proc Natl Acad Sci USA 91:12912–12916PubMedCrossRefGoogle Scholar
  11. 11.
    Magro F, Vieira-Coelho MA, Fraga S, Serrao MP, Veloso FT, Ribeiro T, Soares-da-Silva P (2002) Impaired synthesis or cellular storage of norepinephrine, dopamine, and 5-hydroxytryptamine in human inflammatory bowel disease. Dig Dis Sci 47:216–224PubMedCrossRefGoogle Scholar
  12. 12.
    Magro F, Fraga S, Ribeiro T, Soares-da-Silva P (2004) Decreased availability of intestinal dopamine in transmural colitis may relate to inhibitory effects of interferon-gamma upon L-dopa uptake. Acta Physiol Scand 180:379–386PubMedCrossRefGoogle Scholar
  13. 13.
    Harvey RF, Bradshaw JM (1980) A simple index of Crohn’s disease activity. Lancet 1(8167):514PubMedCrossRefGoogle Scholar
  14. 14.
    Irvine EJ (1995) Usual therapy improves Crohn’s disease as measure a new disease activity index. McMaster Study Group. J Clin Gastroenterol 20:27–32PubMedCrossRefGoogle Scholar
  15. 15.
    Truelove SC, Witts LJ (1995) Cortisone in ulcerative colitis; final report on a therapeutic trial. Br Med J 4947:1041–1048Google Scholar
  16. 16.
    Munkholm P, Langholz E, Davidsen M, Binder V (1994) Frequency of glucocorticoid resistance and dependency in Crohn’s disease. Gut 35:360–362PubMedGoogle Scholar
  17. 17.
    Potocnik U, Ferkolj I, Glavac D, Dean M (2004) Polymorphisms in multidrug resistance 1 (MDR1) gene are associated with refractory Crohn’s disease and ulcerative colitis. Genes and Immunity 5:530–539PubMedCrossRefGoogle Scholar
  18. 18.
    Spitz MR, Shi H, Yang F, Hudmon KS, Jiang H, Chamberlain RM, Amos CI, Wan Y, Cinciripini P, Hong WK, Wu X (1998) Case-control study of the D2 dopamine receptor gene and smoking status in lung cancer patients. J Natl Cancer Inst 90:358–363PubMedCrossRefGoogle Scholar
  19. 19.
    Niessner M, Volk BA (1995) Altered Th1/Th2 cytokine profiles in the intestinal mucosa of patients with inflammatory bowel disease as assessed by quantitative reverse transcribed polymerase chain reaction (RT-PCR). Clin Exp Immunol 101:428–435PubMedCrossRefGoogle Scholar
  20. 20.
    Breese E, Braegger CP, Corrigan CJ (1993). Interleukin-2- and interferon-gamma-secreting T cells in normal and diseased human intestinal mucosa. Immunol Today 78:127–131Google Scholar
  21. 21.
    Papadakis KA, Targan SR (2000) Role of cytokines in the pathogenesis of inflammatory bowel disease. Annu Rev Med 51:289–298PubMedCrossRefGoogle Scholar
  22. 22.
    Peppelenbosch MP, Deventer SJ (2004) T cell apoptosis and inflammatory bowel disease. Gut 53:1556–1558PubMedCrossRefGoogle Scholar
  23. 23.
    Ghosh MC, Mondal AC, Basu S, Banerjee S, Majumber J, Bhattacharya D, Dasgupta PA (2003) Dopamine inhibits cytokine release and expression of tyrosine kinases, LCK and Fyn in activated T cells. Int Immunopharmacol 3:1019–1026PubMedCrossRefGoogle Scholar
  24. 24.
    Denny MF, Patai B, Strauss DB (2000) Differential T-cell antigen receptor signaling mediated by Src family kinases Lck and Fyn. Mol Cell Biol 20:1426–1435PubMedCrossRefGoogle Scholar
  25. 25.
    Qian D, Weiss A (1997) T cell antigen receptor signal transduction. Curr Opin Cell Biol 9:205–212PubMedCrossRefGoogle Scholar
  26. 26.
    Morikawa K, Oseko F, Morikawa S (1994) Immunosuppressive activity of bromocriptine on human T lymphocyte function in vitro. Clin Exp Immunol 95:514–518PubMedCrossRefGoogle Scholar
  27. 27.
    Riskind PN, Massacesi L, Doolittle TH, Hauser SL (1991) The role of prolactin in autoimmune demyelination: suppression of experimental allergic encepalomyelitis by bromocriptine. Ann Neurol 29:542–547PubMedCrossRefGoogle Scholar
  28. 28.
    Bergquist J, Josefsson E, Tarkowski A, Ekman R, Ewing A (1997) Measurements of catecholamine-mediated apoptosis of immunocompetent cells by capillary electrophoresis. Electrophoresis 18:1760–1766PubMedCrossRefGoogle Scholar
  29. 29.
    Colombo C, Cosentino M, Marino F, Rasini E, Ossola M, Blandini F, Mangiagalli A, Samuele A, Ferrari M, Bombelli R, Lecchini S, Nappi G, Frigo G (2003) Dopaminergic modulation of apoptosis in human blood mononuclear cells: possible relevance of Parkinson’s disease. Ann N Y Acad Sci 1010:679–682PubMedCrossRefGoogle Scholar
  30. 30.
    Figueroa FE, Carrion F, Martinnez ME, Rivero S, Mamani L (1997) Bromocriptine induces immunological changes related to disease parameters in rheumatoid arthritis. Br J Rheumatol 36:1022–1023PubMedCrossRefGoogle Scholar
  31. 31.
    McMurray RW, Weidensaul D, Allen SH, Walker SE (1995) Efficacy of bromocriptine in an open label therapeutic trial for systemic lupus erythematosus. J Reumatol 22:2084–2091Google Scholar
  32. 32.
    Weber G, Frey H (1987) Treatment of psoriatic arthritis with bromocriptine. J Am Acad Dermatol 16:388–389PubMedCrossRefGoogle Scholar
  33. 33.
    Kast RE, Altschuler EL (2001) Remission of Crohn’s disease on Bupropion. Gastroenterol 121:1260–1261CrossRefGoogle Scholar
  34. 34.
    Bergquist J, Silberring J (1998) Identification of catecholamines in the immune system by electrospray ionization mass spectrometry. Rapid Commun Mass Spectrom 12:683–688PubMedCrossRefGoogle Scholar
  35. 35.
    Josefsson E, Bergquist J, Ekman R, Tarkowski A (1996) Catecholamines are synthesized by mouse lymphocytes and regulate function of these cells by induction of apoptosis. Immunology 88:140–146PubMedCrossRefGoogle Scholar
  36. 36.
    Tsao CW, Lin YS, Cheng JT (1998) Inhibition of immune cell proliferation with haloporinol and relationship of tyrosine hydroxylase expression to immune cell growth. Life Sci 62:PL335–PL344CrossRefGoogle Scholar
  37. 37.
    Ricci A, Bronzetti E, Felici L, Greco S, Amenta F (1998) Labeling of dopamine D3 and D4 receptor subtypes in human peripheral blood lymphocytes with 3H7-OH-DPAT: a combined radioligand binding assay and immunochemical study. J Neuroimmunol 92:191–195PubMedCrossRefGoogle Scholar
  38. 38.
    Ricci A, Bronzetti E, Mignini F, Tayebati SK, Zaccheo D, Amenta F (1999) Dopamine d1-like receptor subtypes in human peripheral blood lymphocytes. J Neuroimmunol 96:234–240PubMedCrossRefGoogle Scholar
  39. 39.
    Levite M, Chowers Y, Ganor Y, Besser M, Hershkovits R, Cahalon L (2001) Dopamine interacts directly with its D3 and D2 receptors on normal human T cells, and activates beta 1 integrin function. Eur J Immunol 31:3504–3512PubMedCrossRefGoogle Scholar
  40. 40.
    Civelli O, Buzow JR, Grandy DK (1993) Molecular diversity of dopamine receptors. Annu Rev Pharmacol Toxicol 32:281–307CrossRefGoogle Scholar
  41. 41.
    Gingrich JA, Caron MG (1993) Recent advances in molecular biology of dopamine receptors. Annu Rev Neurosci 16:299–321PubMedCrossRefGoogle Scholar
  42. 42.
    Grandy DK, Litt M, Allen L, Bunzow JR, Marchionni M, Makam H, Reed L, Magenis RE, Civelli O (1989) The human D(2) dopamine receptor gene is located on chromosome 11 at q22-q23 and identifies a TaqI RFLP. Am J Hum Genet 45:778–785PubMedGoogle Scholar
  43. 43.
    Noble EP, Blum K, Ritchie T, Montgomery A, Sheridan PJ (1991) Allelic association of the D2 dopamine receptor gene with receptor-binding characteristics in alcoholism. Arch Gen Psych 48:648–654Google Scholar
  44. 44.
    Noble EP, St Jeor ST, Ritchie T, Syndulko K, St Jeor SC, Fitch RJ, Brunner RL, Sparkes RS (1994) D2 dopamine receptor gene and cigarette smoking: a reward gene? Med Hypotheses 42:257–260PubMedCrossRefGoogle Scholar
  45. 45.
    Epstein LH, Wright SM, Paluch RA, Leddy JJ, Hawk LWJ, Jaroni JL, Saad FG, Crystal-Mansour S, Shields PG, Lerman C (2004) Relation between food reinforcement and dopamine genotypes and its effect on food intake in smokers. Am J Clin Nutr 80:82–88PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, Inc. 2006

Authors and Affiliations

  • F. Magro
    • 1
    • 2
    • 6
  • E. Cunha
    • 3
  • F. Araujo
    • 4
  • E. Meireles
    • 4
  • P. Pereira
    • 1
  • M. Dinis-Ribeiro
    • 5
  • F. Tavarela Veloso
    • 1
  • R. Medeiros
    • 3
  • P. Soares-da-Silva
    • 2
  1. 1.Gastroenterology DepartmentPortoPortugal
  2. 2.Institute of Pharmacology and TherapeuticsFaculty of MedicinePortoPortugal
  3. 3.Molecular Oncology/PathologyInstituto Português de OncologiaPortoPortugal
  4. 4.Molecular Biology Center-Hospital S.JoãoPortoPortugal
  5. 5.Department of Biostatistics and Medical Informatics, Faculty of MedicinePortoPortugal
  6. 6.PortoPortugal

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