Lack of interleukin-1α or interleukin-1β inhibits transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice.
Lack of interleukin-1α or interleukin-1β inhibits transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice.
复制标题
DOI：
10.1016/j.jhep.2011.01.048
复制
发表时间：
2011-11
影响因子：
25.7
通讯作者：
Harats D
中科院分区：
文献类型：
--
作者：
Kamari Y;Shaish A;Vax E;Shemesh S;Kandel-Kfir M;Arbel Y;Olteanu S;Barshack I;Dotan S;Voronov E;Dinarello CA;Apte RN;Harats D
鉴定介导非酒精性脂肪性肝炎发展的细胞和分子途径至关重要。由肝脏驻留和浸润的炎性细胞产生的细胞因子在肝脏炎症中起关键作用。促炎性细胞因子IL-1α和IL-1β在脂肪性肝炎中的作用仍不清楚。我们使用IL-1α和IL-1β缺陷小鼠和移植的骨髓细胞来研究肝脏驻留和骨髓来源的IL-1在脂肪变性及其向脂肪性肝炎的进展中的作用。野生型小鼠中致动脉粥样硬化饮食诱导的脂肪性肝炎分别与肝脏IL-1α和IL-1β mRNA水平升高16倍和4.6倍相关。在缺乏IL-1α或IL-1β的小鼠中，脂肪变性向脂肪性肝炎和肝纤维化的转化显著减少。尽管肝脏胆固醇水平升高，但在IL-1α缺陷小鼠中观察到这种保护作用。IL-1α缺乏显著降低了血浆血清淀粉样蛋白A和编码炎症基因（P-选择素、CXCL 1、IL-6、TNFα）以及促纤维化基因（MMP-9和胶原蛋白）的mRNA的稳态水平，特别是TGFβ降低了50%（p=0.004）。与野生型小鼠相比，IL-1β缺陷小鼠中IL-1α mRNA水平低2倍，IL-1α缺陷小鼠中IL-1β转录物低3倍。脂肪性肝炎的发生需要肝细胞来源的IL-1α，而不是来自招募的骨髓来源的细胞。这些数据证明了IL-1α和IL-1β在高胆固醇血症小鼠脂肪变性转化为脂肪性肝炎和肝纤维化中的关键作用。因此，应探索中和IL-1α和/或IL-1β抑制脂肪性肝炎发展的潜力。
The identification of the cellular and molecular pathways that mediate the development of non-alcoholic steatohepatitis is of crucial importance. Cytokines produced by liver-resident and infiltrating inflammatory cells, play a pivotal role in liver inflammation. The role of the proinflammatory cytokines IL-1α and IL-1β in steatohepatitis remains elusive. We employed IL-1α and IL-1β-deficient mice and transplanted marrow cells to study the role of liver-resident and bone marrow-derived IL-1 in steatosis and its progression to steatohepatitis. Atherogenic diet-induced steatohepatitis in wild-type mice was associated with 16 and 4.6 folds-elevations in mRNA levels of hepatic IL-1α and IL-1β, respectively. In mice deficient in either IL-1α or IL-1β the transformation of steatosis to steatohepatitis and liver fibrosis was markedly reduced. This protective effect in IL-1α-deficient mice was noted despite increased liver cholesterol levels. Deficiency of IL-1α markedly reduced plasma serum amyloid A and steady-state levels of mRNA coding for inflammatory genes (P-selectin, CXCL1, IL-6, TNFα) as well as pro-fibrotic genes (MMP-9 and Collagen) and particularly a 50% decrease in TGFβ (p=0.004). IL-1α mRNA levels were 2 folds lower in IL-1β-deficient mice, and IL-1β transcripts were 3 folds lower in IL-1α-deficient compared to wild-type mice. Hepatic cell derived IL-1α rather than from recruited bone marrow-derived cells is required for steatohepatitis development. These data demonstrate the critical role of IL-1α and IL-1β in the transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice. Therefore, the potential of neutralizing IL-1α and/or IL-1β to inhibit development of steatohepatitis should be explored.
登录
查看更多内容
影响因子：
29.4
作者：
Miura K;Kodama Y;Inokuchi S;Schnabl B;Aoyama T;Ohnishi H;Olefsky JM;Brenner DA;Seki E
通讯作者：
Seki E
影响因子：
50.3
作者：
Sakurai T;He G;Matsuzawa A;Yu GY;Maeda S;Hardiman G;Karin M
通讯作者：
Karin M
影响因子：
3.2
作者：
Day, CP
通讯作者：
Day, CP
影响因子：
29
作者：
Mari, Montserrat;Caballero, Francisco;Garcia-Ruiz, Carmen
通讯作者：
Garcia-Ruiz, Carmen
影响因子：
29.7
作者：
Rock KL;Latz E;Ontiveros F;Kono H
通讯作者：
Kono H