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
Department of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Gut. 2006 Mar;55(3):415-24. doi: 10.1136/gut.2005.071118. Epub 2005 Sep 20.
While tumour necrosis factor alpha (TNF-alpha) appears to be associated with the development of non-alcoholic steatohepatitis (NASH), its precise role in the pathogenesis of NASH is not well understood.
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.
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-alpha, 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-alpha 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.
Enhancement of the TNF-alpha/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.
虽然肿瘤坏死因子α（TNF-α）似乎与非酒精性脂肪性肝炎（NASH）的发生有关，但其在NASH发病机制中的精确作用尚未完全明确。
将缺乏肿瘤坏死因子受体1（TNFR1）和2（TNFR2）的雄性小鼠（TNFRDKO小鼠）和野生型小鼠喂食蛋氨酸和胆碱缺乏（MCD）饮食或对照饮食八周，保持能量摄入相同。
与对照野生型小鼠相比，TNFRDKO小鼠喂食MCD饮食八周后肝脂肪变性和纤维化减轻。在肝脏中，MCD饮食喂养后，TNFRDKO小鼠募集的活化肝库普弗细胞数量显著减少。此外，TNFRDKO小鼠肝脏中TNF-α、血管细胞黏附分子1和细胞间黏附分子1的诱导显著受到抑制。在对照动物中，MCD饮食喂养显著增加了全肝和肝星状细胞中金属蛋白酶组织抑制剂1（TIMP-1）的mRNA表达，同时肝星状细胞的活化增强，而在TNFRDKO小鼠中这两个因素均显著降低。在原代培养中，TNF-α给药增强了活化肝星状细胞中TIMP-1 mRNA的表达，并抑制了活化肝星状细胞的凋亡诱导。TIMP-1特异性siRNA抑制TNF诱导的TIMP-1上调可逆转肝星状细胞中的凋亡抑制。
在这个NASH动物模型中，通过自分泌或旁分泌方式激活库普弗细胞增强TNF-α/TNFR介导的信号通路可能在肝纤维化发病机制中起关键作用。
