Journal of Gastroenterology

, Volume 31, Issue 4, pp 538–545 | Cite as

Increased expression of cytokines in liver and serum in patients with extrahepatic diseases

  • Hiroki Fukuma
  • Syed Ahmed Morshed
  • Seishiro Watanabe
  • Naohito Uchida
  • Toru Ezaki
  • Atsushi Minami
  • Hiroshi Matsuoka
  • Shuko Hirabayashi
  • Toshiaki Nakatsu
  • Mikio Nishioka
Liver, Pancreas, and Biliary Tract


To determine whether the liver plays an immunological role in certain extrahepatic disorders, we investigated the expression of interleukin (IL)-1β, IL-6, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α in 11 patients who had recovered from cholecystolithiasis, 12 patients with gastric cancer, 20 patients with chronic hepatitis, and 6 healthy controls. Cytokine mRNAs in the liver were detected by semiquantitative reverse transcribed-polynerase chain reaction. Serum cytokines and soluble IL-2 receptor (sIL-2R) were investigated by enzyme-linked immunosorbent assays. Increases in TNF-α, IL-6, IL-1β, and IFN-γ mRNAs were found in the livers of patients with extrahepatic diseases. TNF-α and IL-6 peptides were increased in the sera of patients with gastric cancer. TNF-α in the sera and TNF-α mRNA in the liver were correlated in gastric cancer patients. Surprisingly, sIL-2R in the serum of gastric cancer patients was significantly higher than the level in healthy controls. Our findings suggest that the liver produces cytokines in reaction to extrahepatic lesions. Further, the increase in sIL-2R in gastric cancer patients indicates that malignancy may affect the immune network in vivo.

Key words

cytokine sIL-2R gastric cancer cholecystolithiasis 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Andus T, Bauer J, Gerok W. Effects of cytokines on the liver. Hepatology 1991;13:364–375.CrossRefPubMedGoogle Scholar
  2. 2.
    Ramadori G, Meyer zum buschenfelde KH. Liver cells and cytokines. Opin Gastroenterol 1993;9:359–366.Google Scholar
  3. 3.
    Balkwill FR, Burke F. The cytokine network. Immunol Today 1989;9:299–304.Google Scholar
  4. 4.
    O'garra A. Interleukins and the immune system 2. Lancet 1989;I:1003–1005.Google Scholar
  5. 5.
    Vilcek J, Lee TH. Tumor necrosis factor. New insights into the molecular mechanisms of its multiple actions. J Biol Chem 1991;266:7313–7316.PubMedGoogle Scholar
  6. 6.
    Arai K, Lee F, Miyajima A, et al. Cytokines: Coordinators of immune and inflammatory responses. Ann Rev Biochem 1990;59:783–836.PubMedGoogle Scholar
  7. 7.
    Fujita T, Reis LFL, Watanabe N, et al. Induction of the transcription factor IRF-1 and interferon-β mRNAs by cytokines and activators of second-messenger pathways. Proc Natl Acad Sci USA 1989;86:9936–9940.PubMedGoogle Scholar
  8. 8.
    Nakazaki H. Preoperative and postoperative cytokines in patients with cancer. Cancer 1992;70:709–713.PubMedGoogle Scholar
  9. 9.
    Luster MI, Germolec DR, Yoshida T, et al. Endotoxin-induced cytokine gene expression and extraction in the liver. Hepatology 1994;19:480–488.CrossRefPubMedGoogle Scholar
  10. 10.
    Tilg H, Wilmer A, Vogel W, et al. Serum levels of cytokines in chronic liver disease. Gastroenterology 1992;103:264–274.PubMedGoogle Scholar
  11. 11.
    Morshed SA, Fukuma H, Kimura Y, et al. Interferon-Γ, interleukin (IL)-2 and IL-2 receptor expressions in hepatitis C virus-infected liver. Gastroenterol Jpn 1993;28(Suppl 5):59–66.PubMedGoogle Scholar
  12. 12.
    Muller C, Knoflach P, Zielinski CC. Soluble interleukin-2 receptor in acute viral hepatitis and chronic liver disease. Hepatology 1989;10:928–932.PubMedGoogle Scholar
  13. 13.
    Wang YF, Wu XN, Zhou YH, et al. Clinical significance of elevated serum soluble interleukin-2 receptor in gastric cancer. Chin Med J 1994;107:254–256.PubMedGoogle Scholar
  14. 14.
    De Groote J, Desmet VJ, Gedigk P, et al. Classification of hepatitis. Lancet 1968;II:626–628.Google Scholar
  15. 15.
    Chomczynsky P, Sacchi N. Single-step method of RNA isolation by acid guanidium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987;162:156–159.Google Scholar
  16. 16.
    Okamoto Y, Shiratori K, Kudo K, et al. Cytokine expression after topical administration of substance P to human nasal mucosa. J Immunol 1993;151:4391–4398.PubMedGoogle Scholar
  17. 17.
    Feber LS, McCloskey TW, Laskin DL. Characterization of interleukin 1 and interleukin 6 production by resident and lipopolysaccharide-activated hepatic macrophages and endothelial cells. In: Wisse E, Knook DL, McCuskey RS (eds) Cells of the hepatic sinusoid, vol III. The Netherlands: Kupffer Cell Foundation, 1991:37–39.Google Scholar
  18. 18.
    Freudenberg MA, Freudenberg N, Galanos C. Time course of cellular distribution of endotoxin in liver, lungs and kidneys of rats. Br J Exp Pathol 1982;63:56–65.PubMedGoogle Scholar
  19. 19.
    Anegon I, Cuturi MC, Trinchieri G et al. Interaction of Fc receptor (CD16) ligands induces transcription of interleukin 2 receptor (CD25) and lymphokine genes and expression of their products in human natural killer cells. J Exp Med 1988;167:452–472.CrossRefPubMedGoogle Scholar
  20. 20.
    Winnock M, Barcina MG, Lucomska B, et al. Liver-associated lymphocytes: Role in tumor defense. Semin Liver Dis 1993;13:81–92.PubMedGoogle Scholar
  21. 21.
    Saito I, Servenius B, Compton T, et al. Detection of Epstein-Barr virus DNA by polymerase chain reaction in blood and tissue biopsies from patient with Sjogren's syndrome. J Exp Med 1989;169:2191–2198.CrossRefPubMedGoogle Scholar
  22. 22.
    Ardizzoia A, Lissoni P, Brivio F, et al. Tumor necrosis factor in solid tumors: Increased blood levels in metastatic disease. J Biol Regul Homeost Agents 1993;6:103–107.Google Scholar
  23. 23.
    Van Meir E, Sawamura Y, Diserens AC, et al. Human glioblastoma cells release interleukin-6 in vivo and in vitro. Cancer Res 1990;50:6683–6688.PubMedGoogle Scholar
  24. 24.
    Watson JM, Sensintaffer JL, Berec JS, et al. Constitutive production of interleukin 6 by ovarian cancer cell lines and by primary ovarian tumor cultures. Cancer Res 1990;50:6959–6965.PubMedGoogle Scholar
  25. 25.
    Siegall CB, Schwab G, Nordan RP, et al. Expression of the interleukin 6 receptor and interleukin 6 in prostate carcinoma cells. Cancer Res 1990;50:7786–7788.PubMedGoogle Scholar
  26. 26.
    Balkwill F, Burke F, Talbot D, et al. Evidence for tumor necrosis factor/cachectin production in cancer. Lancet 1987;II:1229–1232.Google Scholar
  27. 27.
    Malik ST. Tumor necrosis factor: Roles in cancer pathophysiology. Semin Cancer Biol 1992;3:27–33.PubMedGoogle Scholar
  28. 28.
    Napoli J, Bishop GA, McCaughan GW. Increased intrahepatic messenger RNA expression of interleukins 2, 6, and 8 in human cirrhosis. Gastroenterology 1994;107:789–798.PubMedGoogle Scholar
  29. 29.
    Tovey MG, Gugenheim J, Guymarho J, et al. Genes for interleukin-1, interleukin-6 and tumor necrosis factor are expressed at markedly reduced levels in the livers of patients with severe liver disease. Autoimmunity 1991;10:297–310.PubMedGoogle Scholar
  30. 30.
    Wiltrout RH, Herberman RB, Zhang SR, et al. Role of organ-associated NK cells in decreased formation of experimental metastasis in lung and liver. J Immunol 1985;134:4267–4275.PubMedGoogle Scholar
  31. 31.
    O'garra A, Viera P. Polymerase chain reaction for detection of cytokine gene expression. Curr Opin Immunol 1992;4:211–215.CrossRefPubMedGoogle Scholar
  32. 32.
    Fox RI, Kang H, Ando D, et al. Cytokine mRNA expression in salivary gland biopsies of Sjogren's syndrome. J Immunol 1994; 152:5532–5539.PubMedGoogle Scholar

Copyright information

© Springer-Verlag 1996

Authors and Affiliations

  • Hiroki Fukuma
    • 1
  • Syed Ahmed Morshed
    • 1
  • Seishiro Watanabe
    • 1
  • Naohito Uchida
    • 1
  • Toru Ezaki
    • 1
  • Atsushi Minami
    • 1
  • Hiroshi Matsuoka
    • 1
  • Shuko Hirabayashi
    • 1
  • Toshiaki Nakatsu
    • 2
  • Mikio Nishioka
    • 1
  1. 1.Third Department of Internal MedicineKagawa Medical SchoolKagawaJapan
  2. 2.Department of Internal MedicineSt. Martin HospitalKagawaJapan

Personalised recommendations