Cell type-dependent pro- and anti-inflammatory role of signal transducer and activator of transcription 3 in alcoholic liver injury.
OBJECTIVE
Signal transducer and activator of transcription 3 (STAT3) is known to be activated in human alcoholic liver disease, but its role in the pathogenesis of alcoholic liver injury remains obscure.


METHODS
The role of STAT3 in alcoholic liver injury was investigated in hepatocyte-specific STAT3 knockout (H-STAT3KO) mice and macrophage/neutrophil-specific STAT3 KO (M/N-STAT3KO) mice. Alcoholic liver injury was achieved by feeding mice a liquid diet containing 5% ethanol for up to 8 weeks.


RESULTS
Compared with wild-type mice, feeding H-STAT3KO mice with an ethanol-containing diet induced greater hepatic steatosis, hypertriglyceridemia, and hepatic expression of lipogenic genes (sterol regulatory element-binding protein, fatty acid synthase, acetyl-CoA carboxylase-1, and stearoyl-CoA desaturase 1), but less inflammation and lower expression of hepatic proinflammatory cytokines. In contrast, ethanol-fed M/N-STAT3KO mice showed more hepatic inflammation, worse injury, and increased hepatic expression of proinflammatory cytokines compared with wild-type mice. Kupffer cells isolated from ethanol-fed H-STAT3KO mice produced similar amounts of reactive oxygen species and tumor necrosis factor alpha, whereas Kupffer cells from M/N-STAT3KO mice produced more reactive oxygen species and tumor necrosis factor alpha compared with wild-type controls.


CONCLUSIONS
These findings suggest that STAT3 regulates hepatic inflammation in a cell type-dependent manner during alcoholic liver injury: STAT3 in hepatocytes promotes whereas STAT3 in macrophages/Kupffer cells suppresses inflammation. In addition, activation of hepatocellular STAT3 ameliorates alcoholic fatty liver via inhibition of sterol regulatory element-binding protein 1c expression.
Horiguchi
Norio
N
Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
Wang
Lei
L
Mukhopadhyay
Partha
P
Park
Ogyi
O
Jeong
Won Il
WI
Lafdil
Fouad
F
Osei-Hyiaman
Douglas
D
Moh
Akira
A
Fu
Xin Yuan
XY
Pacher
Pál
P
Kunos
George
G
Gao
Bin
B
D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics; D015153:Blotting, Western; D049109:Cell Proliferation; D002492:Central Nervous System Depressants / Q000633:toxicity; D002908:Chronic Disease; D004195:Disease Models, Animal; D000431:Ethanol / Q000633:toxicity; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D007150:Immunohistochemistry; D008104:Liver Cirrhosis, Alcoholic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D054390:Receptors, CCR2 / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000096:biosynthesis / Q000235:genetics
D000943:Antigens, Differentiation; C515335:Ccr2 protein, mouse; D002492:Central Nervous System Depressants; D012333:RNA, Messenger; D054390:Receptors, CCR2; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; C036763:monocyte-macrophage differentiation antigen; D000431:Ethanol