Journal of Gastroenterology

, Volume 30, Issue 1, pp 41–47

Expression rate of cytokine mRNA in the liver of chronic hepatitis C: Comparison with chronic hepatitis B

  • Ryo Fukuda
  • Shuichi Satoh
  • Xuan -Thanh Nguyen
  • Yasushi Uchida
  • Naruaki Kohge
  • Shuji Akagi
  • Satoru Ikeda
  • Makoto Watanabe
  • Shiro Fukumoto
Liver, Pancreas, and Biliary Tract

Abstract

This study was carried out to test the hypothesis that, in chronic hepatitis (CH), inflammatory processes, including viral replication, host immune response, and hepatocyte destruction, are regulated by a cytokine network in the liver. Expression of the mRNA of the cytokines IL1-beta, IL2, IL4, IL5, IL6, TNF-alpha, and IFN-gamma, the lymphocyte markers CD4 and CD8, and the HLA class I molecule, beta 2-microglobulin (B2MG) in the liver tissue of 20 CH(C) cases and 9 CH(B) patients was investigated by the reverse transcription polymerase chain reaction (RT-PCR) method. TNF-alpha, CD4, and B2MG mRNA were detected in 100% of cases of in both CH(B) and CH(C). The expression rates of IL1-beta, IL2, IL4, IFN-gamma, and CD8 mRNA were 80%, 40%, 25%, 40%, and 80% in CH(C) and 88.9%, 44.5%, 30%, 55.6%, and 100% in CH(B). IL6 mRNA was detected only in CH(B), in 22.2% of cases, IL5 mRNA was not detected in either CH(B) or CH(C). IL2, IL4, and IFN-gamma mRNA were expressed significantly more frequently in patients who had high serum ALT and a high histological activity index (HAI) score. There was no difference in cytokine expression between CH(B) and CH(C), except in IL6, suggesting the existence of a common immunopathogenesis for CH(B) and CH(C). In chronic viral hepatitis, IL1-beta and TNF-alpha appear to play a major role in immune responses and IL2, IL4, and IFN-gamma seem to be associated with increased cytotoxic T cell response. Our results give partial support to the hypothesis that the cytokine network is important in the inflammatory process in chronic viral hepatitis in vivo.

Key words

ceytokine mRNA chronic hepatitis RT-PCR 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Davis GL. Interferon treatment of viral hepatitis in immunocompromised patients. Semin Liver Dis 1989;9:267–272.Google Scholar
  2. 2.
    Mondelli M, Alberti A, Tremolada F, et al. In vitro cell-mediated cytotoxity for autologous liver cells in chronic non-A, non-B hepatitis. Clin Exp Immunol 1986;63:147–155.Google Scholar
  3. 3.
    Diens HP, Hutteroth T, Hess G, et al. Immunoelectron microscopic observation of inflammatory infiltrates and HLA antigens in hepatitis B and non-A, non-B. Hepatology 1987;7:1317–1325.Google Scholar
  4. 4.
    Garcia-Monzon C, Mereno-Otero R, Pajares JM, et al. Expression of a novel activation antigen on intrahepatic CD8+ T lymphocytes in viral chronic active hepatitis. Gastroenterology 1990;98:1029–1035.Google Scholar
  5. 5.
    Kita H, Moriyama T, Kaneko T, et al. HLA B44-Restricted cytotoxic T lymphocytes recognizing an epitope on hepatitis C virus nucleocapsid protein. Hepatology 1993;18:1039–1044.Google Scholar
  6. 6.
    Tilg H, Wilmer A, Vogel W, et al. Serum level of cytokines in chronic liver diseases. Gastroenterology 1992;103:264–267.Google Scholar
  7. 7.
    Sheron N, Bird G, Goka J, et al. Elevated plasma interleukin-6 and increased severity and mortality in alcoholic hepatitis. Clin Exp Immunol 1991;84:449–453.Google Scholar
  8. 8.
    Yoshioka K, Kakumu S, Murakami H, et al. Interleukin-2 activity in chronic active liver diseases: Response by T cells and in the autologous mixed lymphocyte reaction. Clin Exp Immunol 1984;56:668–676.Google Scholar
  9. 9.
    Muller C, Zielinski C. Interleukin-6 production by peripheral blood monocytes in patients with chronic liver diseases and acute viral hepatitis. J Hepatol 1992;15:372–377.Google Scholar
  10. 10.
    Nadano S, Kanaoka M, Onji M, et al. Identification of interleukin 1-positive cells in the livers of acute and chronic hepatitis patients. Clin Electron Microscop 1987;20:5–6.Google Scholar
  11. 11.
    Onji M, Kondoh H, Ohta Y. Serial observation of lymphocyte subpopulations and interleukin 2 production of T cells from patients with acute viral hepatitis and chronic active hepatitis. Hepatogastroenterology 1988;35:10–13.Google Scholar
  12. 12.
    Yamaguchi S, Onji M, Ohta Y. Increased serum solble interieukin 2 receptor levels in patients with viral liver diseases. Hepatogastroenterology 1988;35:245–248.Google Scholar
  13. 13.
    Fujioka H. Studies on correlation between mRNA expression of cytokines in the liver and liver biopsy findings in chronic hepatitis C (in Japanese with English abstract). Acta Hepato Jap 1993;34:940–949.Google Scholar
  14. 14.
    Castilla A, Prieto J, Fausto N, et al. Transforming growth factorbeta 1 and alpha in chronic liver disease: Effect of interferon alpha therapy. N Engl J Med 1991;324:933–940.Google Scholar
  15. 15.
    Annoni G, Weiner F, Zern M, et al. Increased transforming growth factor-beta 1 gene expression in human liver diseases. J Hepatolol 1992;14:259–264.Google Scholar
  16. 16.
    Shimada Y, Ichida T, Hasebe C, et al. Peritoneoscopic findings on the liver surface of non-A, non-B chronic hepatitis. Analysis of reddish markings (in Japanese with English abstract). Gastroenterol Endosc 1984;26:671–677.Google Scholar
  17. 17.
    Ohta W. Significane of reddish asteroidal and mesh-work marking on the liver surface of chronic hepatitis observed by peritoneoscopy. Observations of liver cell necrosis in relation to the portal and hepatic veins (in Japanese with English abstract). Acta Hepato Jap 1975;16:448–463.Google Scholar
  18. 18.
    Chomomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate phenol chloroform extraction. Anal Biochem 1987;162:156–159.Google Scholar
  19. 19.
    Chromczynski P. RNAzol B isolation of RNA. Cinna/Biotex Bull 1991. October, No. 3.Google Scholar
  20. 20.
    Fukuda R, Fukumoto S, Shimada Y. A sequential study of viral DNA in serum in experimental transmission of duck hepatitis B virus. J Med Virol 1987;21:311–320.Google Scholar
  21. 21.
    DeGroote J, Desmet VJ, Gedigk P, et al. A classification of chronic hepatitis. Lancet 1968;II:626–628.Google Scholar
  22. 22.
    Knodell RG, Ishak KG, Black WC, et al. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology 1981;1:431–435.Google Scholar
  23. 23.
    Wallace LE, Moss DJ, Rickinson AB, et al. Cytotoxic T cell recognition of Epstein-Barr virus-infected B cells. II. Blocking studies with monoclonal antibodies to HLA determinants. Eur J Immunol 1981;11:694–699.Google Scholar
  24. 24.
    Lakhadar M, Senik A, Fridman WH. Human cytotoxic T lymphocytes (CTL) against Epstein-Barr virus (EBV)-infected cells: EBV specificity and involvement of major histocompatibility complex determinants in lysis exerted by anti-EBV CTL toward HLA compatible and allogeneic target cells. Cell Immunol 1984;83:414–421.Google Scholar
  25. 25.
    Bjorkman PJ, Saper MA, Samraoui B, et al. Structure of the human class I histocompatibility antigen HLA-A2. Nature 1987;329:506–512.Google Scholar
  26. 26.
    Kajino K, Ogawa Y, Michitaka K, et al. Characteristic laparoscopic findings of chronic hepatitis C: A comparison with hepatitis B. Dig Endosc 1991;3:235–239.Google Scholar
  27. 27.
    Emile D, Navaratil E, Devergne O, et al. Monokine gene expression in normal human liver: Selective involvement of the portal compartment. Liver 1992;12:3441–3447.Google Scholar
  28. 28.
    Tovey M, Content J, Gresser I, et al. Genes for IFN-B2 (IL-6), tumor necrosis factor, and IL-1 are expressed at high level in the organs of normal individuals. J Immunol 1988;141:3106–3110.Google Scholar
  29. 29.
    DiGiovine FS, Duff GW. Interleukin-1; the first interleukin. Immunol Today 1990;11:13–20.Google Scholar
  30. 30.
    Nedwin GE, Naylor SL, Sakaguchi AY, et al. Human lymphotoxin and tumor necrotizing factor genes: Structure, homology, and chromosomal localization. Nucleic Acids Res 1985;13:6361–6373.Google Scholar
  31. 31.
    Mosmann TR, Schumacher JH, Street NF, et al. Diversity of cytokine synthesis and function of mouse CD4+ T cells. Immunol Rev 1991;123:209–229.Google Scholar
  32. 32.
    Gillis S, Gillis AE and Hénney C. Monoclonal antibody directed against interleukin 2. I. Inhibition of T lymphocyte mitogenesis and the in vitro differentiation of alloreactive cytolytic T cells. J Exp Med 1981;154:983–988.Google Scholar
  33. 33.
    Tepper RI, Pattengale PK, Leder P. Murine interleukin-4 displays potent anti-tumor activity in vivo. Cell 1989;57:503–512.Google Scholar
  34. 34.
    De Maeyer E, De Maeyer-Guignard J. Interferons and other regulatory cytokines. New York: Wiley and Sons, 1988:448.Google Scholar
  35. 35.
    Nishihara T. Intrahepatic distribution of T cell subsets in cases with type B chronic liver disease by peroxidase-labeled antibody method using monoclonal antibodies. Gastroenterol Jpn 1983;18:320–329.Google Scholar
  36. 36.
    Nagafuchi Y, Scheuer P. Expression of beta 2-microglobulin on hepatocytes in acute and chronic type B hepatitis. Hepatology 1986;6:20–23.Google Scholar
  37. 37.
    Montano L, Miescher GC, Goodall AH, et al. Hepatitis B virus and HLA antigen display in the liver during chronic hepatitis B virus infection. Hepatology 1982;2:557–651.Google Scholar
  38. 38.
    Steinhoff G, Wonigeit K, Pichlmayr R. Analysis of sequential changes in major histocompatibility complex expression in human liver grafts after transplantation. Transplantation 1988;45:394–401.Google Scholar
  39. 39.
    Chu CM, Shyu WC, Kuo RW, et al. HLA class I antigen display on hepatocyte membrane in chronic hepatitis B virus infection: Its role in the pathogenesis of chronic type B hepatitis. Hepatology 1987;7:1311–1316.Google Scholar
  40. 40.
    Lobo-Yeo A, Senaldi G, Portmann B, et al. Class I and class II major histocompatibility complex antigen expression on hepatocytes: A study in children with liver disease. Hepatology 1990;12:224–232.Google Scholar
  41. 41.
    Morita T, Ito T, Ayata K, et al. Analysis of lacal production of inflammatory cytokines in primary biliary cirrhosis by reverse transcription-polymerase chain reaction (in Japanese with English abstract). Acta Hepatol Jap 1922;33:863–871.Google Scholar
  42. 42.
    Hirano T, Akira S, Tage T, et al. Biological and clinical aspects of interleukin 6. Immunol Today 1990;11:443–449.Google Scholar

Copyright information

© Springer-Verlag 1995

Authors and Affiliations

  • Ryo Fukuda
    • 1
  • Shuichi Satoh
    • 1
  • Xuan -Thanh Nguyen
    • 1
  • Yasushi Uchida
    • 1
  • Naruaki Kohge
    • 1
  • Shuji Akagi
    • 1
  • Satoru Ikeda
    • 1
  • Makoto Watanabe
    • 1
  • Shiro Fukumoto
    • 1
  1. 1.Second Department of Internal MedicineShimane Medical UniversityShimaneJapan

Personalised recommendations