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Anti‐Inflammatory and Anti‐Apoptotic Roles of Endothelial Cell STAT3 in Alcoholic Liver Injury
Author(s) -
Miller Andrew M.,
Wang Hua,
Park Ogyi,
Horiguchi Norio,
Lafdil Fouad,
Mukhopadhyay Partha,
Moh Akira,
Fu Xin Yuan,
Kunos George,
Pacher Pal,
Gao Bin
Publication year - 2010
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.2009.01141.x
Subject(s) - stat3 , liver injury , steatosis , apoptosis , alanine transaminase , endocrinology , medicine , stat protein , hepatocyte , inflammation , aspartate transaminase , alcoholic liver disease , endothelial stem cell , knockout mouse , chemistry , biology , biochemistry , in vitro , cirrhosis , receptor , alkaline phosphatase , enzyme
Background: 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 with 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 (SECs). Thus, the purpose of this study was to investigate whether STAT3 in endothelial cells also plays a protective role in alcoholic liver injury. Methods: Wild‐type and endothelial cell‐specific STAT3 knockout (STAT3 E−/− ) mice were pair‐fed and fed ethanol containing diet for 4 weeks. Liver injury and inflammation were determined. Results: Feeding mice with ethanol‐containing diet for 4 weeks induced greater hepatic injury (elevation of serum ALT) and liver weight in STAT3 E−/− mice than wild‐type control groups. In addition, ethanol‐fed STAT3 E−/− mice displayed greater hepatic inflammation and substantially elevated serum and hepatic levels of IL‐6 and TNF‐α compared with wild‐type mice. Furthermore, ethanol‐fed STAT3 E−/− mice displayed a greater abundance of apoptotic SECs and higher levels of serum hyaluronic acid than wild‐type controls. Conclusions: These data suggest that endothelial cell STAT3 plays important dual functions of attenuating hepatic inflammation and SEC death during alcoholic liver injury.