Anti-inflammatory and anti-apoptotic roles of endothelial cell STAT3 in alcoholic liver injury.
Anti-inflammatory and anti-apoptotic roles of endothelial cell STAT3 in alcoholic liver injury.
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DOI：
10.1111/j.1530-0277.2009.01141.x
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发表时间：
2010-04
期刊：
影响因子：
--
通讯作者：
Gao B
中科院分区：
文献类型：
--
作者：
Miller AM;Wang H;Park O;Horiguchi N;Lafdil F;Mukhopadhyay P;Moh A;Fu XY;Kunos G;Pacher P;Gao B
一般认为白介素6(IL-6)的保肝作用是通过激活肝细胞内信号转导和转录激活子3(STAT3)来实现的。IL-6缺陷小鼠更容易发生酒精性肝细胞凋亡和脂肪变性，血清丙氨酸转氨酶(ALT)升高；然而，肝细胞特异性STAT3基因敲除小鼠更容易发生酒精性肝脂肪变性，与野生型小鼠相比，它们在酒精喂养后出现相似的肝细胞凋亡和血清ALT。提示IL-6对酒精性肝损伤的保护作用可能是通过激活肝细胞中的STAT3非依赖性信号或激活非实质细胞中的STAT3来实现的，或者两者兼而有之。我们先前已经证明，IL-6也能激活肝窦内皮细胞中的STAT3。因此，本研究的目的是探讨内皮细胞中的STAT3在酒精性肝损伤中是否也起到保护作用。野生型和内皮细胞特异性STAT3基因敲除(STAT3E−/−)小鼠配对喂养和饲喂含酒精饲料4周。测定肝组织损伤和炎症反应。用含乙醇饲料喂养小鼠4周后，STAT3E−/−小鼠的肝损伤(血清ALT升高)和肝脏重量明显高于野生型对照组。此外，与野生型小鼠相比，酒精喂养的STAT3E−/−小鼠表现出更严重的肝脏炎症，血清和肝脏IL-6和肿瘤坏死因子-α水平显著升高。此外，与野生型对照组相比，酒精喂养的STAT3E−/−小鼠显示出更多的凋亡窦状内皮细胞和更高水平的血清透明质酸。提示血管内皮细胞STAT3在酒精性肝损伤中具有减轻肝脏炎症和肝窦内皮细胞死亡的双重功能。
It is generally believed that the hepatoprotective effect of interleukin-6 (IL-6) is mediated via activation of signal transducer and activator of transcription 3 (STAT3) in hepatocytes. IL-6-deficient mice are more susceptible to alcohol-induced hepatocyte apoptosis and steatosis and elevation of serum alanine transaminase (ALT); however, whereas hepatocyte-specific STAT3 knockout mice are more susceptible to alcohol-induced hepatic steatosis, they have similar hepatocyte apoptosis and serum ALT after alcohol feeding compared to wild-type mice. This suggests that the hepatoprotective effect of IL-6 in alcoholic liver injury may be mediated via activation of STAT3-independent signals in hepatocytes, activation of STAT3 in nonparenchymal cells, or both. We have previously shown that IL-6 also activates STAT3 in sinusoidal endothelial cells. Thus, the purpose of the present study was to investigate whether STAT3 in endothelial cells also plays a protective role in alcoholic liver injury. Wild-type and endothelial cell-specific STAT3 knockout (STAT3E−/−) mice were pair-fed and fed ethanol containing diet for 4 weeks. Liver injury and inflammation were determined. Feeding mice with ethanol containing diet for 4 weeks induced greater hepatic injury (elevation of serum ALT) and liver weight in STAT3E−/− mice than wild-type control groups. In addition, ethanol-fed STAT3E−/− mice displayed greater hepatic inflammation and substantially elevated serum and hepatic levels of IL-6 and TNF-α compared to wild-type mice. Furthermore, ethanol-fed STAT3E−/− mice displayed a greater abundance of apoptotic sinusoidal endothelial cells and higher levels of serum hyaluronic acid than wild-type controls. These data suggest that endothelial cell STAT3 plays important dual functions of attenuating hepatic inflammation and sinusoidal endothelial cell death during alcoholic liver injury.
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DOI：
10.1084/jem.20030077
发表时间：
2003-11-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kano A;Wolfgang MJ;Gao Q;Jacoby J;Chai GX;Hansen W;Iwamoto Y;Pober JS;Flavell RA;Fu XY
通讯作者：
Fu XY
影响因子：
13.5
作者：
Huet, PM;Nagaoka, MR;Bilodeau, M
通讯作者：
Bilodeau, M
影响因子：
6
作者：
Carrithers, M;Tandon, S;Madri, JA
通讯作者：
Madri, JA
影响因子：
2.3
作者：
Gao, B
通讯作者：
Gao, B
影响因子：
13.5
作者：
GIBSON, PR;FRASER, JRE;DUDLEY, FJ
通讯作者：
DUDLEY, FJ