Digestive Diseases and Sciences

, Volume 56, Issue 12, pp 3596–3601 | Cite as

Serum Interleukin-33 Levels in Patients with Gastric Cancer

  • Pinghu Sun
  • Qiwen Ben
  • Shuiping Tu
  • Wenjie Dong
  • Xiaoguang Qi
  • Yunlin Wu
Original Article



Interleukin-33 (IL-33) is a novel member of the IL-1 family of cytokines, and it is closely related to IL-18, one of the best characterized members of the IL-1 family. It’s been demonstrated that elevated levels of IL-18 are involved in a wide variety of tumors, especially in gastric cancer.


The purpose of this study was to determine the correlations between serum IL-33 levels and the clinicopathologic features in gastric cancer patients.


Serum samples were collected from 68 patients with gastric cancer and 57 controls. Serum IL-33 levels were measured by ELISA. Classical tumor markers of CEA and CA19-9 levels were routinely detected by chemiluminescence immunoassay. Western blot analysis was used to detect IL-33 expression in gastric cancer tissue samples and cell lines. The relationship between serum levels of IL-33 and clinical characteristics in patients was analyzed.


IL-33 levels in the serum of gastric cancer patients were significantly elevated in comparison with that of healthy volunteers. Furthermore, higher serum levels of IL-33 in gastric cancer patients were found to correlate with several poor prognostic factors like depth of invasion, distant metastasis and advanced stage (stage III/IV). On the other hand, serum IL-33 levels did not correlate with CEA and CA19-9. The expression of IL-33 protein was upregulated in carcinoma tissues in comparison with matched normal tissues, and no statistically significant difference was found between the four gastric cancer cell lines and human gastric epithelial cell line GES-1.


Serum IL-33 may be a useful biomarker for predicting the prognosis of gastric cancer.


Interleukin-33 Gastric cancer ELISA Prognosis 



We thank Zhongyin Yang, Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine.


  1. 1.
    Pisani P, Parkin DM, Ferlay J. Estimates of the worldwide mortality from eighteen major cancers in 1985. Implications for prevention and projections of future burden. Int J Cancer. 1993;55:891–903.PubMedCrossRefGoogle Scholar
  2. 2.
    Terry MB, Gaudet MM, Gammon MD. The epidemiology of gastric cancer. Semin Radiat Oncol. 2002;12:111–127.PubMedCrossRefGoogle Scholar
  3. 3.
    Ikeguchi M, Hatada T, Yamamoto M, et al. Serum interleukin-6 and -10 levels in patients with gastric cancer. Gastric Cancer. 2009;12:95–100.PubMedCrossRefGoogle Scholar
  4. 4.
    Seguchi T, Yokokawa K, Sugao H, Nakano E, Sonoda T, Okuyama A. Interleukin-6 activity in urine and serum in patients with bladder carcinoma. J Urol. 1992;148:791–794.PubMedGoogle Scholar
  5. 5.
    Fortis C, Foppoli M, Gianotti L, et al. Increased interleukin-10 serum levels in patients with solid tumors. Cancer Lett. 1996;104:1–5.PubMedCrossRefGoogle Scholar
  6. 6.
    Kang JS, Bae SY, Kim HR, et al. Interleukin-18 increases metastasis and immune escape of stomach cancer via the downregulation of CD70 and maintenance of CD44. Carcinogenesis. 2009;30:1987–1996.PubMedCrossRefGoogle Scholar
  7. 7.
    Thong-Ngam D, Tangkijvanich P, Lerknimitr R, Mahachai V, Theamboonlers A, Poovorawan Y. Diagnostic role of serum interleukin-18 in gastric cancer patients. World J Gastroenterol. 2006;12:4473–4477.PubMedGoogle Scholar
  8. 8.
    Haghshenas MR, Hosseini SV, Mahmoudi M, Saberi-Firozi M, Farjadian S, Ghaderi A. IL-18 serum level and IL-18 promoter gene polymorphism in Iranian patients with gastrointestinal cancers. J Gastroenterol Hepatol. 2009;24:1119–1122.PubMedCrossRefGoogle Scholar
  9. 9.
    Carriere V, Roussel L, Ortega N, et al. IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo. Proc Natl Acad Sci USA. 2007;104:282–287.PubMedCrossRefGoogle Scholar
  10. 10.
    Schmitz J, Owyang A, Oldham E, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005;23:479–490.PubMedCrossRefGoogle Scholar
  11. 11.
    Onda H, Kasuya H, Takakura K, et al. Identification of genes differentially expressed in canine vasospastic cerebral arteries after subarachnoid hemorrhage. J Cereb Blood Flow Metab. 1999;19:1279–1288.PubMedCrossRefGoogle Scholar
  12. 12.
    Dinarello CA. Interleukin-1, interleukin-1 receptors and interleukin-1 receptor antagonist. Int Rev Immunol. 1998;16:457–499.PubMedCrossRefGoogle Scholar
  13. 13.
    Park H, Byun D, Kim TS, et al. Enhanced IL-18 expression in common skin tumors. Immunol Lett. 2001;79:215–219.PubMedCrossRefGoogle Scholar
  14. 14.
    Eissa SA, Zaki SA, El-Maghraby SM, Kadry DY. Importance of serum IL-18 and RANTES as markers for breast carcinoma progression. J Egypt Natl Canc Inst. 2005;17:51–55.PubMedGoogle Scholar
  15. 15.
    Merendino RA, Gangemi S, Ruello A, et al. Serum levels of interleukin-18 and sICAM-1 in patients affected by breast cancer: preliminary considerations. Int J Biol Markers. 2001;16:126–129.PubMedGoogle Scholar
  16. 16.
    Lee S, Kang J, Cho M, et al. Profiling of transcripts and proteins modulated by K-ras oncogene in the lung tissues of K-ras transgenic mice by omics approaches. Int J Oncol. 2009;34:161–172.PubMedGoogle Scholar
  17. 17.
    Moussion C, Ortega N, Girard JP. The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel ‘alarmin’? PLoS One. 2008;3:e3331.PubMedCrossRefGoogle Scholar
  18. 18.
    Masamune A, Watanabe T, Kikuta K, Satoh K, Kanno A, Shimosegawa T. Nuclear expression of interleukin-33 in pancreatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 2010;299:G821–G832.PubMedCrossRefGoogle Scholar
  19. 19.
    Kakkar R, Lee RT. The IL-33/ST2 pathway: therapeutic target and novel biomarker. Nat Rev Drug Discov. 2008;7:827–840.PubMedCrossRefGoogle Scholar
  20. 20.
    Trajkovic V, Sweet MJ, Xu D. T1/ST2–an IL-1 receptor-like modulator of immune responses. Cytokine Growth Factor Rev. 2004;15:87–95.PubMedCrossRefGoogle Scholar
  21. 21.
    Gayle MA, Slack JL, Bonnert TP, et al. Cloning of a putative ligand for the T1/ST2 receptor. J Biol Chem. 1996;271:5784–5789.PubMedCrossRefGoogle Scholar
  22. 22.
    Kumar S, Minnich MD, Young PR. ST2/T1 protein functionally binds to two secreted proteins from Balb/c 3T3 and human umbilical vein endothelial cells but does not bind interleukin 1. J Biol Chem. 1995;270:27905–27913.PubMedCrossRefGoogle Scholar
  23. 23.
    Ali S, Huber M, Kollewe C, Bischoff SC, Falk W, Martin MU. IL-1 receptor accessory protein is essential for IL-33-induced activation of T lymphocytes and mast cells. Proc Natl Acad Sci USA. 2007;104:18660–18665.PubMedCrossRefGoogle Scholar
  24. 24.
    Chackerian AA, Oldham ER, Murphy EE, Schmitz J, Pflanz S, Kastelein RA. IL-1 receptor accessory protein and ST2 comprise the IL-33 receptor complex. J Immunol. 2007;179:2551–2555.PubMedGoogle Scholar
  25. 25.
    De Vita F, Orditura M, Galizia G, et al. Serum interleukin-10 levels in patients with advanced gastrointestinal malignancies. Cancer. 1999;86:1936–1943.PubMedCrossRefGoogle Scholar
  26. 26.
    Sharma A, Rajappa M, Saxena A, Sharma M. Cytokine profile in Indian women with cervical intraepithelial neoplasia and cancer cervix. Int J Gynecol Cancer. 2007;17:879–885.PubMedCrossRefGoogle Scholar
  27. 27.
    Choi YS, Choi HJ, Min JK, et al. Interleukin-33 induces angiogenesis and vascular permeability through ST2/TRAF6-mediated endothelial nitric oxide production. Blood. 2009;114:3117–3126.PubMedCrossRefGoogle Scholar
  28. 28.
    Becker CE, O’Neill LA. Inflammasomes in inflammatory disorders: the role of TLRs and their interactions with NLRs. Semin Immunopathol. 2007;29:239–248.PubMedCrossRefGoogle Scholar
  29. 29.
    Kawabata T, Ichikura T, Majima T, et al. Preoperative serum interleukin-18 level as a postoperative prognostic marker in patients with gastric carcinoma. Cancer. 2001;92:2050–2055.PubMedCrossRefGoogle Scholar
  30. 30.
    Iikura M, Suto H, Kajiwara N, et al. IL-33 can promote survival, adhesion and cytokine production in human mast cells. Lab Invest. 2007;87:971–978.PubMedCrossRefGoogle Scholar
  31. 31.
    Salminen A, Kaarniranta K. Glycolysis links p53 function with NF-kappaB signaling: impact on cancer and aging process. J Cell Physiol. 2010;224:1–6.PubMedGoogle Scholar
  32. 32.
    Mancino A, Lawrence T. Nuclear factor-kappaB and tumor-associated macrophages. Clin Cancer Res. 2010;16:784–789.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Pinghu Sun
    • 1
  • Qiwen Ben
    • 2
  • Shuiping Tu
    • 1
  • Wenjie Dong
    • 1
  • Xiaoguang Qi
    • 1
  • Yunlin Wu
    • 1
  1. 1.Department of GastroenterologyRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghaiPeople’s Republic of China
  2. 2.Department of GastroenterologyChanghai Hospital of Second Military Medical UniversityShanghaiPeople’s Republic of China

Personalised recommendations