Estrogen suppresses heptatic IκB expression during short-term alcohol exposure.
OBJECTIVE
To assess the effects of sex steroids on hepatic inflammatory pathways in short-term chronically ethanol-fed rats.


METHODS
Ovariectomized female Wistar rats (8-12 weeks old, n = 8 per treatment group) were implanted with osmotic pumps releasing 17β-estradiol (20 μg/24 h) or testosterone (25 μg/24 h) and fed liquid diets with or without ethanol (8 % w/v) for two weeks. Hepatic expression of IκBα/β, TNF-α, and IL-6 mRNA was examined by real-time PCR. Liver (nuclear) NFκB, IκBα and β, IL-6, and IL-6Rα protein expression was examined by enzyme-linked immunosorbent assay (ELISA) or Western blot.


RESULTS
Estrogen alone induced greater steatosis, NFκB translocation, TNF-α mRNA, as well as IL-6, and IL-6R protein. Alcohol consumption along with estrogen treatment further increased steatosis, NFκB translocation, TNF-α mRNA, and IL-6 protein. Conversely, neither estrogen nor ethanol consumption induced IκBα or IκBβ mRNA or protein expression, while testosterone robustly induced these inhibitory proteins regardless of treatment.


CONCLUSIONS
Estrogen exposure enhances alcohol-induced liver inflammation, and the anti-inflammatory effects of testosterone in the liver might be related to induction of IκB. Elevated inflammation in response to estrogen may overwhelm the regenerative influence of IL-6 in liver, leading to increased steatosis and greater liver damage.
Department of Pharmaceutical Sciences, College of Pharmacy, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73117, USA.
Eric G
EG
Lee
Bethany M
BM
Mickle-Kawar
Lester A
LA
Reinke
Randle M
RM
Gallucci
D000428:Alcohol Drinking / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology*; D000431:Ethanol / Q000008:administration & dosage; D005234:Fatty Liver / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D005260:Female; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D013739:Testosterone / Q000494:pharmacology; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D004967:Estrogens; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D015850:Interleukin-6; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D013739:Testosterone; D004958:Estradiol; D051550:I-kappa B Kinase