Tumour necrosis factor α signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice. Issue 3 (20th September 2005)

• Record Type: Journal Article
• Authors: Tomita, K; Tamiya, G; Ando, S; Ohsumi, K; Chiyo, T; Mizutani, A; Kitamura, N; Toda, K; Kaneko, T; Horie, Y; Han, J-Y; Kato, S; Shimoda, M; Oike, Y; Tomizawa, M; Makino, S; Ohkura, T; Saito, H; Kumagai, N; Nagata, H; Ishii, H; Hibi, T
• Is Part Of: Gut. Volume 55:Issue 3(2006)
• Page Start: 415
• Page End: 424
• Publication Date: 2005-09-20
• Subjects: 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; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gut.2005.071118
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : 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.