title: Cell type-dependent pro- and anti-inflammatory role of signal transducer and activator of transcription 3 in alcoholic liver injury.
abstract: 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.
authors.affiliation: Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland.
authors.forename: Norio
authors.initials: N
authors.lastname: Horiguchi
authors.forename: Lei
authors.initials: L
authors.lastname: Wang
authors.forename: Partha
authors.initials: P
authors.lastname: Mukhopadhyay
authors.forename: Ogyi
authors.initials: O
authors.lastname: Park
authors.forename: Won Il
authors.initials: WI
authors.lastname: Jeong
authors.forename: Fouad
authors.initials: F
authors.lastname: Lafdil
authors.forename: Douglas
authors.initials: D
authors.lastname: Osei-Hyiaman
authors.forename: Akira
authors.initials: A
authors.lastname: Moh
authors.forename: Xin Yuan
authors.initials: XY
authors.lastname: Fu
authors.forename: Pál
authors.initials: P
authors.lastname: Pacher
authors.forename: George
authors.initials: G
authors.lastname: Kunos
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
mesh_terms: 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
chemical_list: 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