Cell type-dependent pro- and anti-inflammatory role of signal transducer and activator of transcription 3 in alcoholic liver injury.

Abstract

BACKGROUND & AIMS:

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: Norio Horiguchi, Lei Wang, Partha Mukhopadhyay, Ogyi Park, Won Il Jeong, Fouad Lafdil, Douglas Osei-Hyiaman, Akira Moh, Xin Yuan Fu, Pál Pacher, George Kunos, Bin Gao
• Journal: Gastroenterology (Gastroenterology) Vol. 134 Issue 4 Pg. 1148-58 (Apr 2008) ISSN: 1528-0012 [Electronic] United States
• PMID: 18395093 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Differentiation
• Ccr2 protein, mouse
• Central Nervous System Depressants
• RNA, Messenger
• Receptors, CCR2
• STAT3 Transcription Factor
• Stat3 protein, mouse
• Sterol Regulatory Element Binding Protein 1
• monocyte-macrophage differentiation antigen
• Ethanol

Topics

• Animals
• Antigens, Differentiation (biosynthesis, genetics)
• Blotting, Western
• Cell Proliferation
• Central Nervous System Depressants (toxicity)
• Chronic Disease
• Disease Models, Animal
• Ethanol (toxicity)
• Gene Expression Regulation
• Hepatocytes (drug effects, metabolism, pathology)
• Immunohistochemistry
• Liver Cirrhosis, Alcoholic (genetics, metabolism, pathology)
• Liver Cirrhosis, Experimental (genetics, metabolism, pathology)
• Mice
• Mice, Knockout
• RNA, Messenger (genetics)
• Receptors, CCR2 (biosynthesis, genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• STAT3 Transcription Factor (genetics, metabolism)
• Sterol Regulatory Element Binding Protein 1 (biosynthesis, genetics)