Anti-inflammatory and anti-apoptotic roles of endothelial cell STAT3 in alcoholic liver injury.
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-alpha 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.
Miller
Andrew M
AM
Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, USA.
Wang
Hua
H
Park
Ogyi
O
Horiguchi
Norio
N
Lafdil
Fouad
F
Mukhopadhyay
Partha
P
Moh
Akira
A
Fu
Xin Yuan
XY
Kunos
George
G
Pacher
Pal
P
Gao
Bin
B
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D000431:Ethanol / Q000633:toxicity; D006519:Hepatitis, Alcoholic / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D015850:Interleukin-6 / Q000172:deficiency; D008108:Liver Diseases, Alcoholic / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D050796:STAT3 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D018836:Inflammation Mediators; D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D000431:Ethanol