Skip to main content
NCBI home page
Clinical and Experimental Immunology logoLink to Clinical and Experimental Immunology
. 1995 Jun;100(3):446–451. doi: 10.1111/j.1365-2249.1995.tb03720.x

The expression of IL-2, IL-4 and interferon-gamma (IFN-gamma) mRNA using liver biopsies at different phases of acute exacerbation of chronic hepatitis B.

R Fukuda 1, N Ishimura 1, T X Nguyen 1, A Chowdhury 1, S Ishihara 1, N Kohge 1, S Akagi 1, M Watanabe 1, S Fukumoto 1
PMCID: PMC1534464  PMID: 7774054

Abstract

To investigate the hypothesis that Th1 phenotype cytokines are associated with the increasing activity of hepatitis and Th2 phenotype cytokines with decreasing activity in the liver of chronic viral hepatitis, expressions of the mRNA of the cytokines IL-2, IFN-gamma and IL-4 in the liver of 23 patients with chronic hepatitis B were investigated by reverse transcription polymerase chain reaction. Patients were divided into three groups according to the phase of acute exacerbation of hepatitis as increasing (n = 9), decreasing (n = 8), and stable phase (n = 6). Both IL-2 and IFN-gamma mRNA were preferentially expressed in increasing phase than in decreasing phase (P < 0.01, P < 0.05, respectively) and associated with the high serum alanine aminotransferase (ALT) level. On the other hand, IL-4 mRNA was detected in decreasing phase with significant frequency compared with increasing phase (P < 0.05). However, expression of IL-4 mRNA was not associated with serum ALT level. Our results suggest that Th1 phenotype cytokines up-regulate and Th2 phenotype cytokines down-regulate the liver inflammation of chronic viral hepatitis.

Full text

PDF
446

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Barnaba V., Balsano F. Immunologic and molecular basis of viral persistence. The hepatitis B virus model. J Hepatol. 1992 Mar;14(2-3):391–400. doi: 10.1016/0168-8278(92)90189-v. [DOI] [PubMed] [Google Scholar]
  2. Barnaba V., Franco A., Paroli M., Benvenuto R., De Petrillo G., Burgio V. L., Santilio I., Balsano C., Bonavita M. S., Cappelli G. Selective expansion of cytotoxic T lymphocytes with a CD4+CD56+ surface phenotype and a T helper type 1 profile of cytokine secretion in the liver of patients chronically infected with Hepatitis B virus. J Immunol. 1994 Mar 15;152(6):3074–3087. [PubMed] [Google Scholar]
  3. Bertoletti A., Ferrari C., Fiaccadori F., Penna A., Margolskee R., Schlicht H. J., Fowler P., Guilhot S., Chisari F. V. HLA class I-restricted human cytotoxic T cells recognize endogenously synthesized hepatitis B virus nucleocapsid antigen. Proc Natl Acad Sci U S A. 1991 Dec 1;88(23):10445–10449. doi: 10.1073/pnas.88.23.10445. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bugeon L., Cuturi M. C., Hallet M. M., Paineau J., Chabannes D., Soulillou J. P. Peripheral tolerance of an allograft in adult rats--characterization by low interleukin-2 and interferon-gamma mRNA levels and by strong accumulation of major histocompatibility complex transcripts in the graft. Transplantation. 1992 Aug;54(2):219–225. doi: 10.1097/00007890-199208000-00006. [DOI] [PubMed] [Google Scholar]
  5. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  6. Del Prete G. F., De Carli M., Ricci M., Romagnani S. Helper activity for immunoglobulin synthesis of T helper type 1 (Th1) and Th2 human T cell clones: the help of Th1 clones is limited by their cytolytic capacity. J Exp Med. 1991 Oct 1;174(4):809–813. doi: 10.1084/jem.174.4.809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dienes H. P., Hütteroth T., Hess G., Meuer S. C. Immunoelectron microscopic observations on the inflammatory infiltrates and HLA antigens in hepatitis B and non-A, non-B. Hepatology. 1987 Nov-Dec;7(6):1317–1325. doi: 10.1002/hep.1840070623. [DOI] [PubMed] [Google Scholar]
  8. Eggink H. F., Houthoff H. J., Huitema S., Gips C. H., Poppema S. Cellular and humoral immune reactions in chronic active liver disease. I. Lymphocyte subsets in liver biopsies of patients with untreated idiopathic autoimmune hepatitis, chronic active hepatitis B and primary biliary cirrhosis. Clin Exp Immunol. 1982 Oct;50(1):17–24. [PMC free article] [PubMed] [Google Scholar]
  9. Fukuda R., Satoh S., Nguyen X. T., Uchida Y., Kohge N., Akagi S., Ikeda S., Watanabe M., Fukumoto S. Expression rate of cytokine mRNA in the liver of chronic hepatitis C: comparison with chronic hepatitis B. J Gastroenterol. 1995 Feb;30(1):41–47. doi: 10.1007/BF01211373. [DOI] [PubMed] [Google Scholar]
  10. García-Monzón C., Moreno-Otero R., Pajares J. M., García-Sánchez A., López-Botet M., de Landázuri M. O., Sánchez-Madrid F. Expression of a novel activation antigen on intrahepatic CD8+ T lymphocytes in viral chronic active hepatitis. Gastroenterology. 1990 Apr;98(4):1029–1035. doi: 10.1016/0016-5085(90)90030-5. [DOI] [PubMed] [Google Scholar]
  11. Hart P. H., Vitti G. F., Burgess D. R., Whitty G. A., Piccoli D. S., Hamilton J. A. Potential antiinflammatory effects of interleukin 4: suppression of human monocyte tumor necrosis factor alpha, interleukin 1, and prostaglandin E2. Proc Natl Acad Sci U S A. 1989 May;86(10):3803–3807. doi: 10.1073/pnas.86.10.3803. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Knodell R. G., Ishak K. G., Black W. C., Chen T. S., Craig R., Kaplowitz N., Kiernan T. W., Wollman J. Formulation and application of a numerical scoring system for assessing histological activity in asymptomatic chronic active hepatitis. Hepatology. 1981 Sep-Oct;1(5):431–435. doi: 10.1002/hep.1840010511. [DOI] [PubMed] [Google Scholar]
  13. Löhr H. F., Gerken G., Schlicht H. J., Meryer zum Büschenfelde K. H., Fleischer B. Low frequency of cytotoxic liver-infiltrating T lymphocytes specific for endogenous processed surface and core proteins in chronic hepatitis B. J Infect Dis. 1993 Nov;168(5):1133–1139. doi: 10.1093/infdis/168.5.1133. [DOI] [PubMed] [Google Scholar]
  14. Löhr H. F., Schlaak J. F., Gerken G., Fleischer B., Dienes H. P., Meyer zum Büschenfelde K. H. Phenotypical analysis and cytokine release of liver-infiltrating and peripheral blood T lymphocytes from patients with chronic hepatitis of different etiology. Liver. 1994 Jun;14(3):161–166. doi: 10.1111/j.1600-0676.1994.tb00067.x. [DOI] [PubMed] [Google Scholar]
  15. Meuer S. C., Moebius U., Manns M. M., Dienes H. P., Ramadori G., Hess G., Hercend T., Meyer zum Büschenfelde K. H. Clonal analysis of human T lymphocytes infiltrating the liver in chronic active hepatitis B and primary biliary cirrhosis. Eur J Immunol. 1988 Sep;18(9):1447–1452. doi: 10.1002/eji.1830180922. [DOI] [PubMed] [Google Scholar]
  16. Missale G., Redeker A., Person J., Fowler P., Guilhot S., Schlicht H. J., Ferrari C., Chisari F. V. HLA-A31- and HLA-Aw68-restricted cytotoxic T cell responses to a single hepatitis B virus nucleocapsid epitope during acute viral hepatitis. J Exp Med. 1993 Mar 1;177(3):751–762. doi: 10.1084/jem.177.3.751. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Mosmann T. R., Coffman R. L. TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol. 1989;7:145–173. doi: 10.1146/annurev.iy.07.040189.001045. [DOI] [PubMed] [Google Scholar]
  18. Nanji A. A., Zhao S., Sadrzadeh S. M., Waxman D. J. Use of reverse transcription-polymerase chain reaction to evaluate in vivo cytokine gene expression in rats fed ethanol for long periods. Hepatology. 1994 Jun;19(6):1483–1487. [PubMed] [Google Scholar]
  19. Nayersina R., Fowler P., Guilhot S., Missale G., Cerny A., Schlicht H. J., Vitiello A., Chesnut R., Person J. L., Redeker A. G. HLA A2 restricted cytotoxic T lymphocyte responses to multiple hepatitis B surface antigen epitopes during hepatitis B virus infection. J Immunol. 1993 May 15;150(10):4659–4671. [PubMed] [Google Scholar]
  20. Paliard X., de Waal Malefijt R., Yssel H., Blanchard D., Chrétien I., Abrams J., de Vries J., Spits H. Simultaneous production of IL-2, IL-4, and IFN-gamma by activated human CD4+ and CD8+ T cell clones. J Immunol. 1988 Aug 1;141(3):849–855. [PubMed] [Google Scholar]
  21. Papp I., Wieder K. J., Sablinski T., O'Connell P. J., Milford E. L., Strom T. B., Kupiec-Weglinski J. W. Evidence for functional heterogeneity of rat CD4+ T cells in vivo. Differential expression of IL-2 and IL-4 mRNA in recipients of cardiac allografts. J Immunol. 1992 Mar 1;148(5):1308–1314. [PubMed] [Google Scholar]
  22. Penna A., Chisari F. V., Bertoletti A., Missale G., Fowler P., Giuberti T., Fiaccadori F., Ferrari C. Cytotoxic T lymphocytes recognize an HLA-A2-restricted epitope within the hepatitis B virus nucleocapsid antigen. J Exp Med. 1991 Dec 1;174(6):1565–1570. doi: 10.1084/jem.174.6.1565. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Peters M., Vierling J., Gershwin M. E., Milich D., Chisari F. V., Hoofnagle J. H. Immunology and the liver. Hepatology. 1991 May;13(5):977–994. [PubMed] [Google Scholar]
  24. Schlaak J. F., Löhr H., Gallati H., Meyer zum Büschenfelde K. H., Fleischer B. Analysis of the in vitro cytokine production by liver-infiltrating T cells of patients with autoimmune hepatitis. Clin Exp Immunol. 1993 Oct;94(1):168–173. doi: 10.1111/j.1365-2249.1993.tb05996.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Scotto J., Hadchouel M., Hery C., Yvart J., Tiollais P., Brechot C. Detection of hepatitis B virus DNA in serum by a simple spot hybridization technique: comparison with results for other viral markers. Hepatology. 1983 May-Jun;3(3):279–284. doi: 10.1002/hep.1840030301. [DOI] [PubMed] [Google Scholar]
  26. Takeuchi T., Lowry R. P., Konieczny B. Heart allografts in murine systems. The differential activation of Th2-like effector cells in peripheral tolerance. Transplantation. 1992 Jun;53(6):1281–1294. [PubMed] [Google Scholar]
  27. Tanaka T., Hu-Li J., Seder R. A., Fazekas de St Groth B., Paul W. E. Interleukin 4 suppresses interleukin 2 and interferon gamma production by naive T cells stimulated by accessory cell-dependent receptor engagement. Proc Natl Acad Sci U S A. 1993 Jul 1;90(13):5914–5918. doi: 10.1073/pnas.90.13.5914. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Thornhill M. H., Haskard D. O. IL-4 regulates endothelial cell activation by IL-1, tumor necrosis factor, or IFN-gamma. J Immunol. 1990 Aug 1;145(3):865–872. [PubMed] [Google Scholar]
  29. Thornhill M. H., Kyan-Aung U., Haskard D. O. IL-4 increases human endothelial cell adhesiveness for T cells but not for neutrophils. J Immunol. 1990 Apr 15;144(8):3060–3065. [PubMed] [Google Scholar]
  30. Tsai S. L., Chen P. J., Lai M. Y., Yang P. M., Sung J. L., Huang J. H., Hwang L. H., Chang T. H., Chen D. S. Acute exacerbations of chronic type B hepatitis are accompanied by increased T cell responses to hepatitis B core and e antigens. Implications for hepatitis B e antigen seroconversion. J Clin Invest. 1992 Jan;89(1):87–96. doi: 10.1172/JCI115590. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Yokota T., Arai N., de Vries J., Spits H., Banchereau J., Zlotnik A., Rennick D., Howard M., Takebe Y., Miyatake S. Molecular biology of interleukin 4 and interleukin 5 genes and biology of their products that stimulate B cells, T cells and hemopoietic cells. Immunol Rev. 1988 Feb;102:137–187. doi: 10.1111/j.1600-065x.1988.tb00744.x. [DOI] [PubMed] [Google Scholar]

Articles from Clinical and Experimental Immunology are provided here courtesy of British Society for Immunology

RESOURCES