Skip to main content
SpringerLink
Log in

Cytokine single nucleotide polymorphisms in patients’ with gallstone: dose TGF-β gene variants affect gallstone formation?

  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Gallstone is a common biliary disorder with several risk factors. Immune responses and inflammatory cytokines are important in this disease; as a result, some cytokines can be detected in bile fluid. In this research, cytokine gene polymorphisms were studied, and their effects on gallstone formation were evaluated. On 158 gallstone patients and 254 normal subjects, by PCR- RFLP method, IL-4-C590T polymorphism and by ARMS-PCR method, IFN-γ T+874A, TNF-α-A308G, IL-6 G-174C and TGF-β T+869C variants were studied. Pathologic evaluations were done on surgical specimens. There were no significant differences in distribution of evaluated polymorphisms between patient group and normal control group (P > 0.05), except TGF-β +869T allele (P = 0.04, OR = 1.23, 95 % CI = 1–1.79) which was higher in patients with gallstone. Although the pro-inflammatory cytokines such as TNF-α and IL-6 may promote gallstone formation, in this study no significant correlation between TNF-α and IL-6 polymorphisms and gallstone formation was seen. It is taught that TGF-β may affect gallbladder cells to promote gallstone formation and higher producer TGF-β +869T allele can be a risk factor of gallstone disease, so further studies would be more elucidative.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Mittal B, Mittal R (2002) Genetics of gallstone disease. J Postgrad Med 48:149–152

    PubMed  CAS  Google Scholar 

  2. Maurer KJ, Carey MC, Fox JG (2009) Roles of infection, inflammation, and the immune system in cholesterol gallstone formation. Gastroenterology 136:425–440

    Article  PubMed  CAS  Google Scholar 

  3. Caddy GR, Kirby J, Kirk SJ, Allen MJ, Moorehead RJ, Tham TC (2005) Natural history of asymptomatic bile duct stones at time of cholecystectomy. Ulst Med J 74:108–112

    CAS  Google Scholar 

  4. Bennion LJ, Grundy SM (1978) Risk factors for development of cholelithiasis in man. N Eng J Med 299:1221–1227

    Article  CAS  Google Scholar 

  5. Maclure KM, Hayes KC, Colditz GA, Stampfer MJ, Speizer FE, Willett WC (1989) Weight, diet and the risk of symptomatic gallstones in middle aged women. N Engl J Med 321:563–569

    Article  PubMed  CAS  Google Scholar 

  6. Carey MC, Paigen B (2002) Epidemiology of the American Indians’ burden and its likely genetic origins. Hepatology 36:781–791

    PubMed  CAS  Google Scholar 

  7. Khanuja B, Cheah YC, Hunt M, Nishina PM, Wang DQ, Chen HW, Billheimer JT, Carey MC, Paigen B (1995) Lith1, a major gene affecting cholesterol gallstone formation among inbred strains of mice. Proc Natl Acad Sci USA 92:7729–7733

    Article  PubMed  CAS  Google Scholar 

  8. Sánchez-Cuén J, Aguilar-Medina M, Arámbula-Meraz E, Romero-Navarro J, Granados J, Sicairos-Medina L, Ramos-Payán R (2010) ApoB-100, ApoE and CYP7A1 gene polymorphisms in Mexican patients with cholesterol gallstone disease. World J Gastroenterol 16:4685–4690

    Article  PubMed  Google Scholar 

  9. Rosen HR, Winkle PJ, Kendall BJ, Diehl DL (1997) Biliary interleukin-6 and tumor necrosis factor-a in patients undergoing endoscopic retrograde cholangiopancreatography. Dig Dis Sci 42:1290–1294

    Article  PubMed  CAS  Google Scholar 

  10. Savard CE, Blinman TA, Choi HS, Lee SK, Pandol SJ, Lee SP (2002) Expression of cytokine and chemokine mRNA and secretion of tumor necrosis factor alpha by gallbladder epithelial cells: response to bacterial lipopolysaccharides. BMC Gastroenterol 2:23

    Article  PubMed  Google Scholar 

  11. Reynoso-Paz S, Coppel RL, Mackay IR, Bass NM, Ansari AA, Gershwin ME (1999) The immunobiology of bile and biliary epithelium. Hepatology 30:351 (Review)

    Article  PubMed  CAS  Google Scholar 

  12. Papadakis KA, Targan SR (2000) Tumor necrosis factor: biology and therapeutic inhibitors. Gastroenterology 119:1148–1157

    Article  PubMed  CAS  Google Scholar 

  13. Rege RF (2000) Inflammatory cytokines alter human gallbladder epithelial cell absorption/secretion. J Gastrointest Surg 4:185–192

    Article  PubMed  CAS  Google Scholar 

  14. Daneshmandi S, Pourfathollah AA, Pourpak Z, Heidarnazhad H, Kalvanagh PA (2012) Cytokine gene polymorphism and asthma susceptibility, progress and control level. Mol Biol Rep 39:1845–1853

    Article  PubMed  CAS  Google Scholar 

  15. Imboden M, Nieters A, Bircher AJ, Brutsche M, Becker N, Wjst M, Ackermann-Liebrich U, Berger W, Probst-Hensch NM (2006) Cytokine gene polymorphisms and atopic disease in two European cohorts (ECRHS-Basel and SAPALDIA). Clin Mol Allergy 4:1–9

    Article  Google Scholar 

  16. Gupta V, Sehajpal PK (2003) Rapid detection of single nucleotide (−308) polymorphism in TNF-α promoter using ARMS-PCR. Curr Sci 85:1521–1523

    CAS  Google Scholar 

  17. Fishman D, Faulds G, Jeffery R, Mohamed-Ali V, Yudkin JS, Humphries S, Woo P (1998) The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. J Clin Invest 102:1369–1376

    Article  PubMed  CAS  Google Scholar 

  18. Arkwright PD, Chase JM, Babbage S, Pravica V, David TJ, Hutchinson IV (2001) Atopic dermatitis is associated with a low-producer transforming growth factor β1 cytokine genotype. J Allergy Clin Immunol 108:281–284

    Article  PubMed  CAS  Google Scholar 

  19. Vishnoi M, Pandey SN, Choudhury G, Kumar A, Modi DR, Mittal B (2007) Do TNFA −308 G/A and IL6 −174 G/C gene polymorphisms modulate risk of gallbladder cancer in the north Indian population? Asian Pac J Cancer Prev 8:567–572

    PubMed  Google Scholar 

  20. Vishnoi M, Choudhuri G, Mittal B (2007) Is IL-10-819C/T gene polymorphism modulating the risk of gallbladder disease in north Indian population? J Gastrointest Cancer 38:46–51

    Article  PubMed  CAS  Google Scholar 

  21. Finzi L, Barbu V, Burgel PR, Mergey M, Kirkwood KS, Wick EC, Scoazec JY, Peschaud F, Paye F, Nadel JA, Housset C (2006) MUC5AC, a gel-forming mucin accumulating in gallstone disease, is overproduced via an epidermal growth factor receptor pathway in the human gallbladder. Am J Pathol 169:2031–2041

    Article  PubMed  CAS  Google Scholar 

  22. Zen Y, Harada K, Sasaki M, Tsuneyama K, Katayanagi K, Yamamoto Y, Nakanuma Y (2002) Lipopolysaccharide induces overexpression of MUC2 and MUC5AC in cultured biliary epithelial cells: possible key phenomenon of hepatolithiasis. Am J Pathol 161:1475–1484

    Article  PubMed  CAS  Google Scholar 

  23. Swidsinski A, Khilkin M, Pahlig H, Swidsinski S, Priem F (1998) Time dependent changes in the concentration and type of bacterial sequences found in cholesterol gallstones. Hepatology 27:662–665

    Article  PubMed  CAS  Google Scholar 

  24. Savard CE, Blinman TA, Choi HS, Lee SK, Pandol SJ, Lee SP (2002) Expression of cytokine and chemokine mRNA and secretion of tumor necrosis factor-alpha by gallbladder epithelial cells: response to bacterial lipopolysaccharides. BMC Gastroenterol 2:23

    Article  PubMed  Google Scholar 

  25. Van Erpecum KJ (2011) Pathogenesis of cholesterol and pigment gallstones: an update. Clin Res Hepatol Gastroenterol 35:281–287

    Article  PubMed  Google Scholar 

  26. Kitasato A, Tajima Y, Kuroki T, Tsutsumi R, Adachi T, Mishima T, Kanematsu T (2007) Inflammatory cytokines promote inducible nitric oxide synthase-mediated DNA damage in hamster gallbladder epithelial cells. World J Gastroenterol 13:6379–6384

    Article  PubMed  CAS  Google Scholar 

  27. Novovic S, Andersen AM, Ersbøll AK, Nielsen OH, Jorgensen LN, Hansen MB (2009) Proinflammatory cytokines in alcohol or gallstone induced acute pancreatitis: a prospective study. JOP 10:256–262

    PubMed  Google Scholar 

  28. Ezure T, Sakamoto T, Tsuji H, Lunz JG, Murase N, Fung JJ, Demetris AJ (2000) The development and Compensation of Biliary Cirrhosis in Interleukin-6-Deficient Mice. Am J Pathol 156:1627–1639

    Article  PubMed  CAS  Google Scholar 

  29. King Victoria L, Szilvassy Stephen J, Daugherty A (2002) Interleukin-4 deficiency promotes gallstone formation. J Lipid Res 43:768–771

    PubMed  CAS  Google Scholar 

  30. Ishige K, Shoda J, Kawamoto T, Matsuda S, Ueda T, Hyodo I, Ohkohchi N, Puri RK, Kawakami K (2008) Potent in vitro and in vivo antitumor activity of interleukin-4-conjugated pseudomonas exotoxin against human biliary tract carcinoma. Int J Cancer 123:2915–2922

    Article  PubMed  CAS  Google Scholar 

  31. Narumoto K, Saibara T, Maeda T, Onishi S, Hayashi Y, Miyazaki E, Hiroi M, Enzan H, Kobayashi N (2000) Transforming growth factor-beta 1 derived from biliary epithelial cells may attenuate alloantigen-specific immune responses. Transpl Int 13:21–27

    PubMed  CAS  Google Scholar 

  32. Kitamura K, Kasuya K, Tsuchida A, Mimuro A, Inoue K, Aoki T, Aoki T, Koyanagi Y (2003) Immunohistochemical analysis transforming growth factor beta in gallbladder cancer. Oncol Rep 10:327–332

    PubMed  CAS  Google Scholar 

  33. Mori M, Miyazaki K (2000) Factors affecting morphogenesis of rabbit gallbladder epithelial cells cultured in collagen gels. Cell Tissure Res 300:331–344

    Article  CAS  Google Scholar 

  34. Asano T, Shoda J, Ueda T, Kawamoto T, Todoroki T, Shimonishi M, Tanabe T, Sugimoto Y, Ichikawa A, Mutoh M, Tanaka N, Miwa M (2002) Expressions of cyclooxygenase-2 and prostaglandin E-receptors in carcinoma of the gallbladder: crucial role of arachidonate metabolism in tumor growth and progression. Clin Cancer Res 8:1157–1167

    PubMed  CAS  Google Scholar 

  35. Köninger J, di Mola FF, Di Sebastiano P, Gardini A, Brigstock DR, Innocenti P, Büchler MW, Friess H (2005) Transforming growth factor-b pathway is activated in cholecystolithiasis. Langenbecks Arch Surg 390:21–28

    Article  PubMed  Google Scholar 

  36. Choi HS, Savard CE, Choi JW, Kuver R, Lee SP (2007) Paclitaxel interrupts TGF-beta1 signaling between gallbladder epithelial cells and myofibroblasts. J Surg Res 141:183–191

    Article  PubMed  CAS  Google Scholar 

  37. Vishnoi M, Pandey SN, Choudhuri G, Mittal B (2008) IL-1 gene polymorphisms and genetic susceptibility of gallbladder cancer in a north Indian population. Cancer Genet Cytogenet 186:63–68

    Article  PubMed  CAS  Google Scholar 

  38. Vishnoi M, Pandey SN, Modi DR, Kumar A, Mittal B (2008) Genetic susceptibility of epidermal growth factor +61A>G and transforming growth factor beta1 −509C>T gene polymorphisms with gallbladder cancer. Hum Immunol 69:360–367

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors are grateful to the Department of Immunology of Tarbiat Modares University and Islamic Azad University, Kazerun branch for financial support.

Author information

Authors and Affiliations

  1. Biochemistry Department, School of Medicine, Kazerun Branch, Islamic Azad University, Kazerun, Iran

    Padideh Ebadi

  2. Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

    Saeed Daneshmandi

  3. Alborz Hospital, Social Organization, Karaj, Iran

    Abbas Ghasemi

  4. Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran

    Mohammad Hossein Karimi

Authors
  1. Padideh Ebadi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Saeed Daneshmandi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Abbas Ghasemi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mohammad Hossein Karimi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Padideh Ebadi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ebadi, P., Daneshmandi, S., Ghasemi, A. et al. Cytokine single nucleotide polymorphisms in patients’ with gallstone: dose TGF-β gene variants affect gallstone formation?. Mol Biol Rep 40, 6255–6260 (2013). https://doi.org/10.1007/s11033-013-2737-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-013-2737-6

Keywords

Search

Navigation