Advertisement

Digestive Diseases and Sciences

, Volume 54, Issue 3, pp 683–689 | Cite as

Clinical Significance of Interleukin-6 (Il-6) Gene Polymorphism and Il-6 Serum Level in Pancreatic Adenocarcinoma and Chronic Pancreatitis

  • Renata Talar-WojnarowskaEmail author
  • Anita Gasiorowska
  • Beata Smolarz
  • Hanna Romanowicz-Makowska
  • Andrzej Kulig
  • Ewa Malecka-Panas
Original Article

Abstract

The aim of our study was to assess the clinical significance of -174G/C Il-6 gene polymorphism and Il-6 serum level in patients with pancreatic adenocarcinoma (PA) and chronic pancreatitis (CP). The study included 41 with pancreatic adenocarcinoma, 56 with chronic pancreatitis, and 50 healthy volunteers, hospitalized between 2003 and 2006. Il-6 serum levels were measured with an enzyme-linked immunoassay and Il-6 gene polymorphism was studied in DNA isolated from peripheral blood. In PA and CP patients Il-6 serum levels were significantly higher than in the control group (P < 0.01). The levels of Il-6 in the patients with tumor size ≥3.5 cm were higher than that in patients with smaller tumors (P < 0.01). The elevated Il-6 levels were also correlated with the presence of liver metastases (P < 0.01). Mean Il-6 serum level was significantly higher in patients homozygous G/G for -174 Il-6 gene compared with patients with at least one C allele. Our findings indicate that -174G/C Il-6 gene polymorphism influences circulating Il-6 levels. Increased Il-6 serum levels may be correlated with tumor size and the presence of liver metastases in patients with pancreatic adenocarcinoma.

Keywords

Interleukin-6 Polymorphism Pancreatic adenocarcinoma Chronic pancreatitis 

Notes

Acknowledgment

Work supported by Medical University of Lodz, Poland grant 502-11-537.

References

  1. 1.
    Lotz M (1993) Interleukin-6. Cancer Invest 11:732–742. doi: 10.3109/07357909309046948 PubMedCrossRefGoogle Scholar
  2. 2.
    Ohzato H, Yoshizaki K, Nishimoto N, Ogata A, Tagoh H, Monden M et al (1992) Interleukin-6 as a new indicator of inflammatory status: detection of serum levels of interleukin-6 and C-reactive protein after surgery. Surgery 111:201–209PubMedGoogle Scholar
  3. 3.
    Damas P, Ledoux D, Nys M, Wrindts Y, De Groote D, Franchimont P et al (1992) Cytokine serum level during severe sepsis in human Il-6 as a marker of severity. Ann Surg 215:356–362PubMedCrossRefGoogle Scholar
  4. 4.
    Fishman D, Faulds G, Jeffery R, Mohamed-Ali U, Yudkin JS, Humpherces S (1998) The effect of novel polymorphisms in the interleukine-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. doi: 10.1172/JCI2629 PubMedCrossRefGoogle Scholar
  5. 5.
    Dosquet C, Schaetz A, Faucher C, Lepage E, Wautier JL, Richard A et al (1994) Tumor necrosis factor-α, interleukin-1β and interleukin-6 in patients with renal cell carcinoma. Eur J Cancer 30:162–167. doi: 10.1016/0959-8049(94)90079-5 CrossRefGoogle Scholar
  6. 6.
    Okada S, Okusaka T, Ishii H, Kyogoku A, Yoshimori M, Kajimura N et al (1998) Elevated serum interleukin-6 levels in patients with pancreatic cancer. Jpn J Clin Oncol 28:12–15. doi: 10.1093/jjco/28.1.12 PubMedCrossRefGoogle Scholar
  7. 7.
    Wu CW, Wang SR, Chao MF, Wu TC (1996) Serum interleukin-6 levels reflect disease status of gastric cancer. Am J Gastroenterol 91:1417–1422PubMedGoogle Scholar
  8. 8.
    Lai R, O’Brien S, Maushouri T, Rogers A, Kantarijan H, Keating M et al (2002) Prognostic value of plasma interleukin-6 levels in patients with chronic lymphocytic leukemia. Cancer 95:1071–1075. doi: 10.1002/cncr.10772 PubMedCrossRefGoogle Scholar
  9. 9.
    Takeda K, Fujii N, Nitta Y, Sakihara H, Nakyama K, Rikishi H et al (1991) Murine tumor cells metastasizing selectively in the liver: ability to produce hepatocyte-activating cytokines interleukin-1 and/or -6. Jpn J Cancer Res 82:1299–1308PubMedGoogle Scholar
  10. 10.
    Tabibzadeh SS, Poubouridis D, May LT, Sehgal PB (1989) Interleukin-6 immunoreactivity in human tumors. Am J Pathol 135:427–433PubMedGoogle Scholar
  11. 11.
    DeMichele A, Martin AM, Mick R, Gor P, Wray L, Klein-Cabral M et al (2003) Interleukin-6174 G/C polymorphism is associated with improved outcome in high-risk breast cancer. Cancer Res 63:8051–8056PubMedGoogle Scholar
  12. 12.
    Nikiteas N, Tzanakis N, Gazouli M, Rallis G, Danilidis K, Theodoropoulus G et al (2005) Serum Il-6, TNF alpha and CRP levels in Greek colorectal cancer patients: prognosis implications. World J Gastroenterol 11:1639–1643PubMedGoogle Scholar
  13. 13.
    Bowcock AM, Kidd JR, Lathrop GM, Daneshvar L, May L, Ray A et al (1988) The human “interferon-beta 2/hepatocyte stimulating factor/interleukin-6” gene: DNA polymorphism studies and localization to chromosome 7p21. Genomics 3:8–16. doi: 10.1016/0888-7543(88)90152-8 PubMedCrossRefGoogle Scholar
  14. 14.
    Haddy N, Sass C, Maumus S, Marie B, Droesch S, Siest G, Visvikis S et al (2005) Biological variations, genetic polymorphisms and familial resemblance of TNF-alpha and Il-6 concentrations: STANISLAS cohort. Eur J Hum Genet 13:109–117. doi: 10.1038/sj.ejhg.5201294 PubMedCrossRefGoogle Scholar
  15. 15.
    Hefler LA, Crimm C, Ackermann S, Malur S, Radjabi-Rahat AR, Leodolter S et al (2003) An interleukin-6 gene promoter polymorphism influences the biological phenotype of ovarian cancer. Cancer Res 63:3066–3068PubMedGoogle Scholar
  16. 16.
    Belluco C, Olivieri F, Bonafe M, Giovagnetti S, Mammano E, Scalrta R et al (2003) 174G>C polymorphism of interleukin 6 gene promoter affects interleukin 6 serum level in patients with colorectal cancer. Clin Cancer Res 9:2173–2176PubMedGoogle Scholar
  17. 17.
    Barber MD, Powell JJ, Lynch SF, Fearon KH, Ross JA (2000) A polymorphism of the interleukin-1β gene influences survival in pancreatic cancer. Br J Cancer 83:1443–1447. doi: 10.1054/bjoc.2000.1479 PubMedCrossRefGoogle Scholar
  18. 18.
    Ebrahimi B, Tucker SL, Li D, Abbruzzese JM, Kurzrock R (2004) Cytokines in pancreatic carcinoma. Correlation with phenotypic characteristics and prognosis. Cancer 101:2727–2736. doi: 10.1002/cncr.20672 PubMedCrossRefGoogle Scholar
  19. 19.
    Sarner M, Cotton PB (1983) Classifications of pancreatitis. International Workshop, vol 25. King`s College, Cambridge, pp 756–759Google Scholar
  20. 20.
    Landi S, Moreno V, Gioia-Patricola L, Guino E, Navarro M, Oca J et al (2003) Association of common polymorphisms in inflammatory genes interleukin (Il)-6, Il-8, tumor necrosis factor alpha, NFKB1 and peroxisome proliferator-activated receptor γ with colorectal cancer. Cancer Res 63:3560–3566PubMedGoogle Scholar
  21. 21.
    Goydos JS, Brumfield AM, Frezza E, Booth A, Lotze MT, Carty SE (1998) Marked elevation of serum interleukin-6 in patients with cholangiocarcinoma. Ann Surg 227:398–404. doi: 10.1097/00000658-199803000-00012 PubMedCrossRefGoogle Scholar
  22. 22.
    Bemelmans MA, Gouma DJ, Greve JW, Burman WA (1992) Cytokines, tumor necrosis factor and interleukin-6 in experimental biliary obstruction in mice. Hepatology 15:1132–1136. doi: 10.1002/hep. 1840150626 PubMedCrossRefGoogle Scholar
  23. 23.
    Oka M, Yamamoto K, Takahashi M, Hakozaki M, Abe T, Lizuka N et al (1996) Relationship between serum levels of interleukin 6, various diseases parameters and malnutrition in patients with esophageal squamous cell carcinoma. Cancer Res 56:2776–2780PubMedGoogle Scholar
  24. 24.
    Falconer JS, Fearon KC, Plester CE, Ross JA, Carter DC (1994) Cytokines, the acute-phase response and resting energy expenditure in cachectic patients with pancreatic cancer. Ann Surg 219:325–331. doi: 10.1097/00000658-199404000-00001 PubMedCrossRefGoogle Scholar
  25. 25.
    Kinoshita T, Ito H, Miki C (1999) Serum interleukin-6 level reflects the tumor proliferative activity in patients with colorectal carcinoma. Cancer 85:2526–2531. doi:10.1002/(SICI)1097-0142(19990615)85:12<2526::AID-CNCR6>3.0.CO;2-3 PubMedCrossRefGoogle Scholar
  26. 26.
    Tanner J, Tosato G (1991) Impairment of natural killer functions by interleukin 6 increases lymphoblastoid cell tumorigenicity in athymic mice. J Clin Invest 88:239–247. doi: 10.1172/JCI115283 PubMedCrossRefGoogle Scholar
  27. 27.
    Wigmore SJ, Fearon KC, Sangster K, Maingay JP, Garden OJ, Ross JA (2002) Cytokine regulation of constitutive production of interleukin-8 and -6 by human pancreatic cancer cell lines and serum cytokine concentrations in patients with pancreatic cancer. Int J Oncol 21:881–886PubMedGoogle Scholar
  28. 28.
    Bhatnagar A, Wig JD, Majumdar S (2003) Immunological findings in acute and chronic pancreatitis. J Surg 73:59–64Google Scholar
  29. 29.
    Szuster-Ciesielska A, Daniluk J, Kandefer-Zerszen M (2000) Serum levels of cytokines in alcoholic liver cirrhosis and pancreatitis. Arch Immunol Ther Exp (Warsz) 48:301–307Google Scholar
  30. 30.
    Bomba T, Yoshioka U, Inoue H, Iwasaki Y, Hosoda S (1994) Serum levels of interleukin-1 beta and interleukin-6 in patients with chronic pancreatitis. J Gastroenterol 29:314–319. doi: 10.1007/BF02358371 CrossRefGoogle Scholar
  31. 31.
    Bonafe M, Olivieri F, Cavallone L, Giovagnetti S, Marchegiani F, Cardelli M et al (2001) A gender-dependent genetic predisposition to produce high levels of Il-6 is detrimental for longevity. Eur J Immunol 31:2357–2361. doi:10.1002/1521-4141(200108)31:8<2357::AID-IMMU2357>3.0.CO;2-XPubMedCrossRefGoogle Scholar
  32. 32.
    Bendicho MT, Guedes JC, Silva NN, Santana GO, Sanot RR, Lyra AC et al (2005) Polymorphism of cytokine genes (TGF-beta1, INF-gamma, Il-6, Il-10 and TNF-alpha) in patients with chronic pancreatitis. Pancreas 30:333–336. doi: 10.1097/01.mpa.0000161809.24284.33 PubMedCrossRefGoogle Scholar
  33. 33.
    Foster CB, Lehrnbecher T, Samuels S, Stein S, Mol F, Metcalf JA et al (2000) An Il-6 promoter polymorphism is associated with a lifetime risk of development of Kaposi sarcoma in men infected with immunodeficiency virus. Blood 96:2562–2567PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Renata Talar-Wojnarowska
    • 1
    Email author
  • Anita Gasiorowska
    • 1
  • Beata Smolarz
    • 2
  • Hanna Romanowicz-Makowska
    • 2
  • Andrzej Kulig
    • 2
  • Ewa Malecka-Panas
    • 1
  1. 1.Department of Digestive Tract DiseasesMedical University of LodzLodzPoland
  2. 2.Laboratory of Molecular GeneticsInstitute of Polish Mother’s Memorial HospitalLodzPoland

Personalised recommendations