Tumor necrosis factor- signalling through activation of Kupffer cells plays an essential role in liver fibrosis of nonalcoholic steatohepatitis in mice

Kengo Tomita ¹, Gen Tamiya ², Satoshi Ando ², Kayoko Ohsumi ³, Tomoko Chiyo ¹, Akiko Mizutani ⁴, Naoto Kitamura ¹, Kyoko Toda ⁵, Takehiko Kaneko ¹, Yoshinori Horie ¹, Jing-Yan Han ¹, Shinzo Kato ¹, Masayuki Shimoda ⁶, Yuichi Oike ⁷, Maiko Tomizawa ², Satoshi Makino ², Tamiko Ohkura ³, Hidetsugu Saito ¹, Naoki Kumagai ⁸, Hiroshi Nagata ¹, Hiromasa Ishii ¹ and Toshifumi Hibi ^1*

¹ Department of Internal Medicine, Keio University School of Medicine, Japan
² Department of Neurology, Tokushima University Graduate School of Medicine, Japan
³ Institute for Advanced Medical Research, Keio University School of Medicine, Japan
⁴ Department of Molecular Life Science, School of Medicine, Tokai University, Japan
⁵ Biomedical Laboratory, Kitasato Institute Hospital, Japan
⁶ Department of Pathology, Keio University School of Medicine, Japan
⁷ Department of Cell Differentiation, Keio University School of Medicine, Japan
⁸ Research Center for Liver Disease, Kitasato Institute Hospital, Japan

^* To whom correspondence should be addressed. E-mail: thibi{at}sc.itc.keio.ac.jp.

Accepted 31 August 2005

Abstract

Background: While tumor necrosis factor (TNF)-& [alpha] appears to be associated with the development of nonalcoholic 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 wks maintaining isoenergetic intake.

Results: MCD dietary feeding of TNFRDKO mice for eight wks resulted in attenuated liver steatosis and fibrosis in comparison 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-, vascular cell adhesion molecule (VCAM)-1, and intracellular adhesion molecule (ICAM)-1 was significantly suppressed in TNFRDKO mice. While in control animals, MCD dietary feeding dramatically increased mRNA expression of tissue inhibitor of metalloproteinase (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- 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-/TNFR- mediated signaling 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.

Keywords: Kupffer cell, liver fibrosis, nonalcoholic steatohepatitis, tissue inhibitor of metalloproteinase-1, tumor necrosis factor-alpha

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