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Tumour necrosis factor α signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice
  1. K Tomita1,
  2. G Tamiya2,
  3. S Ando2,
  4. K Ohsumi3,
  5. T Chiyo1,
  6. A Mizutani4,
  7. N Kitamura1,
  8. K Toda5,
  9. T Kaneko1,
  10. Y Horie1,
  11. J-Y Han1,
  12. S Kato1,
  13. M Shimoda6,
  14. Y Oike7,
  15. M Tomizawa2,
  16. S Makino2,
  17. T Ohkura3,
  18. H Saito1,
  19. N Kumagai8,
  20. H Nagata1,
  21. H Ishii1,
  22. T Hibi1
  1. 1Department of Internal Medicine, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
  2. 2Department of Neurology, Tokushima University Graduate School of Medicine, Tokushima, Japan
  3. 3Institute for Advanced Medical Research, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
  4. 4Department of Molecular Life Science, School of Medicine, Tokai University, Bohseidai, Isehara, Kanagawa, Japan
  5. 5Biomedical Laboratory, Kitasato Institute Hospital, Shirokane, Minato-ku, Tokyo, Japan
  6. 6Department of Pathology, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
  7. 7Department of Cell Differentiation, Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
  8. 8Research Center for Liver Disease, Kitasato Institute Hospital, Shirokane, Minato-ku, Tokyo, Japan
  1. Correspondence to:
    Dr T Hibi
    Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan; thibi{at}


Background: While tumour necrosis factor α (TNF-α) appears to be associated with the development of non-alcoholic steatohepatitis (NASH), its precise role in the pathogenesis of NASH is not well understood.

Methods: Male mice deficient in both TNF receptors 1 (TNFR1) and 2 (TNFR2) (TNFRDKO mice) and wild-type mice were fed a methionine and choline deficient (MCD) diet or a control diet for eight weeks, maintaining isoenergetic intake.

Results: MCD dietary feeding of TNFRDKO mice for eight weeks resulted in attenuated liver steatosis and fibrosis compared with control wild-type mice. In the liver, the number of activated hepatic Kupffer cells recruited was significantly decreased in TNFRDKO mice after MCD dietary feeding. In addition, hepatic induction of TNF-α, vascular cell adhesion molecule 1, and intracellular adhesion molecule 1 was significantly suppressed in TNFRDKO mice. While in control animals MCD dietary feeding dramatically increased mRNA expression of tissue inhibitor of metalloproteinase 1 (TIMP-1) in both whole liver and hepatic stellate cells, concomitant with enhanced activation of hepatic stellate cells, both factors were significantly lower in TNFRDKO mice. In primary cultures, TNF-α administration enhanced TIMP-1 mRNA expression in activated hepatic stellate cells and suppressed apoptotic induction in activated hepatic stellate cells. Inhibition of TNF induced TIMP-1 upregulation by TIMP-1 specific siRNA reversed the apoptotic suppression seen in hepatic stellate cells.

Conclusions: Enhancement of the TNF-α/TNFR mediated signalling pathway via activation of Kupffer cells in an autocrine or paracrine manner may be critically involved in the pathogenesis of liver fibrosis in this NASH animal model.

  • TNF-α, tumour necrosis factor α
  • NASH, non-alcoholic steatohepatitis
  • ASH, alcoholic steatohepatitis
  • TNFR, tumour necrosis factor receptor
  • TNFRDKO mice, mice deficient in both TNFR1 and TNFR2
  • MCD, methionine and choline deficient
  • VCAM, vascular cell adhesion molecule
  • ICAM, intracellular adhesion molecule
  • PHB, prohibitin
  • COX, cytochrome oxidase subunit
  • TIMP, tissue inhibitor of metalloproteinase
  • TGF-β, transforming growth factor β
  • SREBP, sterol regulatory response element binding protein
  • SCD, stearoyl-CoA desaturase
  • FAS, fatty acid synthase
  • HSD, hydroxysteroid dehydrogenase
  • MTTP, microsomal triglyceride transfer protein
  • TG, triglyceride
  • ALT, alanine aminotransferase
  • mAb, monoclonal antibody
  • EMEM, Eagle’s minimum essential medium
  • FBS, fetal bovine serum
  • LPS, lipopolysaccharide
  • tumour necrosis factor-α
  • non-alcoholic steatohepatitis
  • tissue inhibitor of metalloproteinase 1
  • kupffer cell
  • liver fibrosis

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  • Published online first 20 September 2005

  • Conflict of interest: None declared.

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