Ethanol inhibits the JAK-STAT signaling pathway in freshly isolated rat hepatocytes but not in cultured hepatocytes or HepG2 cells: evidence for a lack of involvement of ethanol metabolism.
OBJECTIVE
To understand the molecular mechanism underlying alcoholic liver injury, effects of acute ethanol on the Janus kinase-signal transducer and activator transcription factor (JAK-STAT) signaling in hepatic cells were studied.


METHODS
Effects of acute ethanol on the JAK-STAT signaling in freshly isolated, cultured rat hepatocytes, and HepG2 cells were explored.


RESULTS
Acute ethanol exposure inhibited IL-6- or IFN-activated STAT in freshly isolated hepatocytes but not in cultured hepatocytes, HepG2 cells, or HepG2 cells transfected with alcohol dehydrogenase (ADH) or cytochrome P450(2E1). The inhibitory action of ethanol in freshly isolated hepatocytes was not antagonized by the ADH inhibitor 4-methylpyrazole (4-MP). Acute exposure of hepatocytes to acetaldehyde or hydrogen peroxide did not suppress STAT activation. Further studies indicated that the loss of response to the inhibitory effect of ethanol was not due to hepatocyte proliferation and collagen contact.


CONCLUSIONS
Freshly isolated hepatocytes are more susceptible to the inhibitory action of ethanol on the JAK-STAT signaling than cultured hepatocytes or HepG2 cells, which may be implicated in pathogenesis and progression of alcoholic liver disease.
Chen
J
J
Department of Pharmacology & Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298, USA.
Clemens
D L
DL
Cederbaum
A I
AI
Gao
B
B
D000079:Acetaldehyde / Q000494:pharmacology; D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics; D000818:Animals; D002455:Cell Division; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D019392:Cytochrome P-450 CYP2E1 / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000378:metabolism / Q000494:pharmacology*; D000077604:Fomepizole; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008297:Male; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D014157:Transcription Factors / Q000378:metabolism*
D004791:Enzyme Inhibitors; D015850:Interleukin-6; D011720:Pyrazoles; D014157:Transcription Factors; D000431:Ethanol; D007371:Interferon-gamma; D000077604:Fomepizole; D003094:Collagen; D006861:Hydrogen Peroxide; D000426:Alcohol Dehydrogenase; D019392:Cytochrome P-450 CYP2E1; D011505:Protein-Tyrosine Kinases; D000079:Acetaldehyde