TY - JOUR
T1 - Anti-inflammatory and anti-apoptotic roles of endothelial cell STAT3 in alcoholic liver injury
AU - Miller, Andrew M.
AU - Wang, Hua
AU - Park, Ogyi
AU - Horiguchi, Norio
AU - Lafdil, Fouad
AU - Mukhopadhyay, Partha
AU - Moh, Akira
AU - Fu, Xin Yuan
AU - Kunos, George
AU - Pacher, Pal
AU - Gao, Bin
PY - 2010/4
Y1 - 2010/4
N2 - 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 (STAT3E-/-) 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 STAT3E-/- 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 STAT3E-/- 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.
AB - 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 (STAT3E-/-) 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 STAT3E-/- 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 STAT3E-/- 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.
KW - Alcoholic Liver Injury
KW - Endothelial Cells
KW - IL-6
KW - STAT3
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U2 - 10.1111/j.1530-0277.2009.01141.x
DO - 10.1111/j.1530-0277.2009.01141.x
M3 - Article
C2 - 20102572
AN - SCOPUS:77949975840
SN - 0145-6008
VL - 34
SP - 719
EP - 725
JO - Alcoholism: Clinical and Experimental Research
JF - Alcoholism: Clinical and Experimental Research
IS - 4
ER -