Tumour necrosis factor α signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice

K. Tomita, G. Tamiya, S. Ando, K. Ohsumi, T. Chiyo, A. Mizutani, N. Kitamura, K. Toda, T. Kaneko, Y. Horie, J. Y. Han, Shinzo Kato, Masayuki Shimoda, Y. Oike, M. Tomizawa, S. Makino, T. Ohkura, Hidetsugu Saito, N. Kumagai, H. Nagata & 2 others H. Ishii, T. Hibi

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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.

Original languageEnglish
Pages (from-to)415-424
Number of pages10
JournalGut
Volume55
Issue number3
DOIs
Publication statusPublished - 2006 Mar

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Kupffer Cells
Fatty Liver
Liver Cirrhosis
Hepatic Stellate Cells
Tumor Necrosis Factor-alpha
Tissue Inhibitor of Metalloproteinase-1
Choline
Methionine
Liver
Diet
Messenger RNA
Vascular Cell Adhesion Molecule-1
Tumor Necrosis Factor Receptors
Small Interfering RNA
Hepatocytes
Up-Regulation
Animal Models

ASJC Scopus subject areas

  • Gastroenterology

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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. / Tomita, K.; Tamiya, G.; Ando, S.; Ohsumi, K.; Chiyo, T.; Mizutani, A.; Kitamura, N.; Toda, K.; Kaneko, T.; Horie, Y.; Han, J. Y.; Kato, Shinzo; Shimoda, Masayuki; Oike, Y.; Tomizawa, M.; Makino, S.; Ohkura, T.; Saito, Hidetsugu; Kumagai, N.; Nagata, H.; Ishii, H.; Hibi, T.

In: Gut, Vol. 55, No. 3, 03.2006, p. 415-424.

Research output: Contribution to journalArticle

Tomita, K, Tamiya, G, Ando, S, Ohsumi, K, Chiyo, T, Mizutani, A, Kitamura, N, Toda, K, Kaneko, T, Horie, Y, Han, JY, Kato, S, Shimoda, M, Oike, Y, Tomizawa, M, Makino, S, Ohkura, T, Saito, H, Kumagai, N, Nagata, H, Ishii, H & Hibi, T 2006, 'Tumour necrosis factor α signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice', Gut, vol. 55, no. 3, pp. 415-424. https://doi.org/10.1136/gut.2005.071118
Tomita, K. ; Tamiya, G. ; Ando, S. ; Ohsumi, K. ; Chiyo, T. ; Mizutani, A. ; Kitamura, N. ; Toda, K. ; Kaneko, T. ; Horie, Y. ; Han, J. Y. ; Kato, Shinzo ; Shimoda, Masayuki ; Oike, Y. ; Tomizawa, M. ; Makino, S. ; Ohkura, T. ; Saito, Hidetsugu ; Kumagai, N. ; Nagata, H. ; Ishii, H. ; Hibi, T. / Tumour necrosis factor α signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice. In: Gut. 2006 ; Vol. 55, No. 3. pp. 415-424.
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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.",
author = "K. Tomita and G. Tamiya and S. Ando and K. Ohsumi and T. Chiyo and A. Mizutani and N. Kitamura and K. Toda and T. Kaneko and Y. Horie and Han, {J. Y.} and Shinzo Kato and Masayuki Shimoda and Y. Oike and M. Tomizawa and S. Makino and T. Ohkura and Hidetsugu Saito and N. Kumagai and H. Nagata and H. Ishii and T. Hibi",
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T1 - Tumour necrosis factor α signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice

AU - Tomita, K.

AU - Tamiya, G.

AU - Ando, S.

AU - Ohsumi, K.

AU - Chiyo, T.

AU - Mizutani, A.

AU - Kitamura, N.

AU - Toda, K.

AU - Kaneko, T.

AU - Horie, Y.

AU - Han, J. Y.

AU - Kato, Shinzo

AU - Shimoda, Masayuki

AU - Oike, Y.

AU - Tomizawa, M.

AU - Makino, S.

AU - Ohkura, T.

AU - Saito, Hidetsugu

AU - Kumagai, N.

AU - Nagata, H.

AU - Ishii, H.

AU - Hibi, T.

PY - 2006/3

Y1 - 2006/3

N2 - 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.

AB - 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.

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DO - 10.1136/gut.2005.071118

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EP - 424

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SN - 0017-5749

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