, 31:215 | Cite as

Hepatoprotective Effect of Infliximab, an Anti-TNF-α Agent, on Carbon Tetrachloride-Induced Hepatic Fibrosis

  • Ibrahim Halil Bahcecioglu
  • Suleyman Serdar Koca
  • Orhan Kursat Poyrazoglu
  • Mehmet Yalniz
  • Ibrahim Hanifi Ozercan
  • Bilal Ustundag
  • Kazim Sahin
  • Adile Ferda Dagli
  • Ahmet Isik


To assess the effect of infliximab, an anti-tumor necrosis factor (TNF)-α agent, on the carbon tetrachloride (CCl4)-induced hepatic fibrosis in rats. Rats were randomized into three groups (n = 9). The control group received only intraperitoneal (i.p.) olive oil. Hepatic fibrosis was induced by repeated i.p. injections of 1.5 ml/kg CCl4 (1:3 mixture with olive oil) for 5 weeks in the remaining two groups which were also injected subcutaneous saline or 2 mg/kg infliximab. Infliximab reduced the levels of aspartate aminotransferase and alanine aminotransferase (p < 0.05 for both). The scores of hepatic necrosis, inflammation and fibrosis, and expression of α-smooth muscle actin were lower in the infliximab-treated group than the CCI4-treated group (p < 0.01, p < 0.001, p < 0.01, p < 0.001, respectively). However, there was no significant difference in terms of liver tissue and plasma malondialdehyde, and serum TNF-α levels, while infliximab relatively reduced the level of transforming growth factor-β1 (373.0 ± 153.1 vs. 280.8 ± 127.1 pg/ml). Treatment with infliximab attenuated the necro-inflammation and fibrogenesis in the CCI4-induced hepatic fibrosis, and thus it might be effective as a therapeutic anti-fibrotic agent.


carbon tetrachloride hepatic fibrosis infliximab 


  1. 1.
    Friedman, S. L. 2003. Liver fibrosis—from bench to bedside. J. Hepatol. 38:S38–S53.PubMedCrossRefGoogle Scholar
  2. 2.
    Ogawa, K., J. Suzuki, H. Mukai, and M. Mori. 1986. Sequential changes of extracellular matrix and proliferation of Ito cells with enhanced expression of desmin and actin in focal hepatic injury. Am. J. Pathol. 125:611–619.PubMedGoogle Scholar
  3. 3.
    Maher, J. J. 1999. Leukocytes as modulators of stellate cell activation. Alcohol Clin. Exp. Res. 23:917–921.PubMedGoogle Scholar
  4. 4.
    Gressner, A. M., B. Lahme, and A. Brenzel. 1995. Molecular dissection of the mitogenic effect of hepatocytes on cultured hepatic stellate cells. Hepatology 22:1507–1518.PubMedGoogle Scholar
  5. 5.
    Recknagel, R., E. A. Glende, J. A. Dolak, and R. L. Waller. 1989. Mechanisms of carbon tetrachloride toxicity. Pharma. Ther. 43:139–154.CrossRefGoogle Scholar
  6. 6.
    Brattin, W. J., E. A. Glende, and R. O. Recknagel. 1985. Pathological mechanisms in carbon tetrachloride hepatotoxicity. J. Free Radic. Biol. Med. 1:27–28.PubMedCrossRefGoogle Scholar
  7. 7.
    Nadkarni, G. D., and N. B. D’Souza. 1988. Hepatic antioxidant enzymes and lipid peroxidation in carbon tetrachloride-induced liver cirrhosis in rats. Biochem. Med. Metabol. Biol. 40:42–45.CrossRefGoogle Scholar
  8. 8.
    Gassó, M., M. Rubio, G. Varela, M. Cabré, J. Caballería, E. Alonso, R. Deulofem, J. Camps, A. Giménez, M. Pajares, A. Parés, J. M. Mato, and J. Rodés. 1996 Effects of S-adenosylmethionine on lipid peroxidation and liver fibrogenesis in carbon tetrachloride-induced cirrhosis. J. Hepatol. 25:200–205.Google Scholar
  9. 9.
    Simeonova, P. P., R. M. Gallucci, T. Hulderman, R. Wilson, C. Kommineni, M. Rao, and M. I. Luster. 2001. The role of tumor necrosis factor-a in liver toxicity, inflammation, and liver fibrosis induced by carbontetrachloride. Toxicol. Appl. Pharmacol. 177:112–120.PubMedCrossRefGoogle Scholar
  10. 10.
    Wanner, G. A., P. E. Müller, W. Ertel, M. Bauer, M. D. Menger, and K. Messmer. 1999. Differential effect of anti-TNF-alpha antibody on proinflammatory cytokine release by Kupffer cells following liver ischemia and reperfusion. Shock 11:391–395.PubMedCrossRefGoogle Scholar
  11. 11.
    Gallucci, R. M., P. P. Simeneova, W. Toriumi, and M. I. Luster. 2000. TNF alpha regulates transforming growth factor-alpha expression in regenerating murine liver and isolated hepatocytes. J. Immunol. 164:872–878.PubMedGoogle Scholar
  12. 12.
    Yagi, K. 1984. Assay for blood plasma or serum. Methods Enzymol 105:328–331.PubMedCrossRefGoogle Scholar
  13. 13.
    Satoh, K., S. Takamatsu, S. Sakuta, S. Mizuno, H. Metoki, and M. Takamatsu. 1981. Augmented malondialdehyde production by platelets from patients with cerebrovascular disorders. Jpn. Circ. J. 45:1335–1341.PubMedGoogle Scholar
  14. 14.
    Ohkawa, H., N. Ohishi, and K. Yagi. 1979. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Annal. Biochem. 95:351–358.CrossRefGoogle Scholar
  15. 15.
    Koca, S. S., I. H. Bahcecioglu, O. K. Poyrazoglu, I. H. Ozercan, K. Sahin, and B. Ustundag. 2007. The treatment with antibody of TNF-alpha reduces the inflammation, necrosis and fibrosis in the non-alcoholic steatohepatitis induced by methionine- and choline-deficient diet. Inflammation 31:91–98, Dec 8; [Epub ahead of print].Google Scholar
  16. 16.
    Lee, K. S., S. J. Lee, H. J. Park, J. P. Chung, K. H. Han, C. Y. Chon, S. I. Lee, and Y. M. Moon. 2001. Oxidative stress effect on the activation of hepatic stellate cells. Yonsei Med. J. 42:1–8.PubMedGoogle Scholar
  17. 17.
    Edwards, M. J., B. J. Keller, F. C. Kaufman, and R. G. Thurman. 1993. The involvement of Kupffer cells in carbon tetrachloride toxicity. Toxicol. Appl. Pahrmacol. 119:275–279.CrossRefGoogle Scholar
  18. 18.
    Brouckaert, P., and W. Fiers. 1996. Tumor necrosis factor and the systemic inflammatory response syndrome. Curr. Top. Microbiol. Immunol. 216:167–187.PubMedGoogle Scholar
  19. 19.
    Tilg, H. 1993. The role of cytokines in the pathophysiology of chronic liver diseases. Int. J. Clin. Lab. Res. 23:179–185.PubMedCrossRefGoogle Scholar
  20. 20.
    Wullaert, A., K. Heyninck, and R. Beyaert. 2006. Mechanisms of crosstalk between TNF-induced NF-kappaB and JNK activation in hepatocytes. Biochem. Pharmacol. 72:1090–1101.PubMedCrossRefGoogle Scholar
  21. 21.
    Sudo, K., Y. Yamada, H. Moriwaki, K. Saito, and M. Seishima. 2005. Lack of tumor necrosis factor receptor type 1 inhibits liver fibrosis induced by carbon tetrachloride in mice. Cytokine 29:236–244.PubMedCrossRefGoogle Scholar
  22. 22.
    Czaja, M. J., J. Xu, and E. Alt. 1995. Prevention of carbon tetrachloride-induced rat liver injury by tumor necrosis factor receptor. Gastroenterology 108:1849–1854.PubMedCrossRefGoogle Scholar
  23. 23.
    Kimura, K., K. Ando, H. Ohnishi, T. Ishikawa, S. Kakumu, M. Takemura, Y. Muto, and H. Moriwaki. 1999. Immunopathogenesis of hepatic fibrosis in chronic liver injury induced by repeatedly administered concanavalin A. Int. Immunol. 11:1491–1500.PubMedCrossRefGoogle Scholar
  24. 24.
    Gurujeyalakshmi, G., and S. N. Giri. 1995. Molecular mechanisms of antifibrotic effect of interferon gamma in bleomycin-mouse model of lung fibrosis: downregulation of TGF-beta and procollagen I and III gene expression. Exp. Lung Res. 2:791–808.CrossRefGoogle Scholar
  25. 25.
    Shen, H., M. Zhang, G. Y. Minuk, and Y. Gong. 2002. Different effects of rat interferon alpha, beta and gamma on rat hepatic stellate cell proliferation and activation. BMC Cell. Biol. 3:9.PubMedCrossRefGoogle Scholar
  26. 26.
    Natsume, M., H. Tsuji, A. Harada, M. Akiyama, T. Yano, H. Ishikura, I. Nakanishi, K. Matsushima, S. Kaneko, and N. Mukaida. 1999. Attenuated liver fibrosis and depressed serum albumin levels in carbon tetrachloride-treated IL-6-deficient mice. J. Leukoc. Biol. 66:601–608.PubMedGoogle Scholar
  27. 27.
    Roderfeld, M., A. Geier, C. G. Dietrich, E. Siewert, B. Jansen, C. Gartung, and E. Roeb. 2006. Cytokine blockade inhibits hepatic tissue inhibitor of metalloproteinase-1 expression and up-regulates matrix metalloproteinase-9 in toxic liver injury. Liver Int. 26:579–586.PubMedCrossRefGoogle Scholar
  28. 28.
    Murray, D. A., and I. N. Crispe. 2004. TNF-alpha controls intrahepatic T cell apoptosis and peripheral T cell numbers. J. Immunol. 173:2402–2409.PubMedGoogle Scholar
  29. 29.
    Lang, A., R. Schoonhoven, S. Tuvia, D. A. Brenner, and R. A. Rippe. 2000. Nuclear factor kappaB in proliferation, activation, and apoptosis in rat hepatic stellate cells. J. Hepatol. 33:49–58.PubMedCrossRefGoogle Scholar
  30. 30.
    Freedman, A. R., R. J. Sharma, G. J. Nabel, S. G. Emerson, and G. E. Griffin. 1992. Cellular distribution of nuclear factor kappa B binding activity in rat liver. Biochem. J. 287:645–649.PubMedGoogle Scholar
  31. 31.
    Piguet, P. F., and C. Vesin. 1994. Treatment by human recombinant soluble TNF receptor of pulmonary fibrosis induced by bleomycin or silica in mice. Eur. Respir. J. 7:515–518.PubMedCrossRefGoogle Scholar
  32. 32.
    Koca, S. S., A. Isik, I. H. Ozercan, B. Ustundag, B. Evren, and K. Metin. 2008. Effectiveness of etanercept in bleomycin-induced experimental scleroderma. Rheumatology (Oxford) 47:172–175.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Ibrahim Halil Bahcecioglu
    • 1
  • Suleyman Serdar Koca
    • 2
    • 6
  • Orhan Kursat Poyrazoglu
    • 1
  • Mehmet Yalniz
    • 1
  • Ibrahim Hanifi Ozercan
    • 3
  • Bilal Ustundag
    • 4
  • Kazim Sahin
    • 5
  • Adile Ferda Dagli
    • 3
  • Ahmet Isik
    • 2
  1. 1.Department of Gastroenterology, Faculty of MedicineFırat UniversityElazigTurkey
  2. 2.Department of Internal Medicine and Rheumatology, Faculty of MedicineFırat UniversityElazigTurkey
  3. 3.Department of Pathology, Faculty of MedicineFırat UniversityElazigTurkey
  4. 4.Department of Biochemistry, Faculty of MedicineFırat UniversityElazigTurkey
  5. 5.Department of Animal Nutrition, Faculty of VeterinaryFırat UniversityElazigTurkey
  6. 6.Tıp Fakultesi, RomatolojiFırat universitesiElazigTurkey

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