title: Gender differences in early alcohol-induced liver injury: role of CD14, NF-kappaB, and TNF-alpha.
abstract: The purpose of this study was to determine whether early alcohol-induced liver injury (ALI) in females is associated with changes in CD14 on Kupffer cells, activation of hepatic nuclear factor (NF)-kappaB, and expression of tumor necrosis factor (TNF)-alpha mRNA. Male and female rats were given high-fat control or ethanol-containing diets for 4 wk using the intragastric enteral protocol. Physiological parameters were similar in both genders. Ethanol was increased as tolerance developed with higher blood levels than previously observed, resulting in a fourfold increase in aspartate aminotransferase (males 389 +/- 47 IU/l vs. females 727 +/- 66 IU/l). Hepatic pathology developed more rapidly and was nearly twofold greater and endotoxin levels were significantly higher in females after ethanol. Also, expression of CD14 on Kupffer cells was 1.5-fold greater and binding of transcription factor NF-kappaB in hepatic nuclear extracts and TNF-alpha mRNA expression were threefold greater in females. These data are consistent with the hypothesis that elevated endotoxin after ethanol triggers more activation of Kupffer cells via enhanced CD14 expression in females. NF-kappaB is activated in this process, leading to increases in TNF-alpha mRNA expression in the liver and more severe liver injury in females. It is concluded that gender differences in ALI are dependent on endotoxin and a signaling cascade leading to TNF-alpha.
authors.affiliation: Laboratory of Hepatobiology and Toxicology, Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599-7365, USA.
authors.forename: H
authors.initials: H
authors.lastname: Kono
authors.forename: M D
authors.initials: MD
authors.lastname: Wheeler
authors.forename: I
authors.initials: I
authors.lastname: Rusyn
authors.forename: M
authors.initials: M
authors.lastname: Lin
authors.forename: V
authors.initials: V
authors.lastname: Seabra
authors.forename: C A
authors.initials: CA
authors.lastname: Rivera
authors.forename: B U
authors.initials: BU
authors.lastname: Bradford
authors.forename: D T
authors.initials: DT
authors.lastname: Forman
authors.forename: R G
authors.initials: RG
authors.lastname: Thurman
mesh_terms: D000818:Animals; D001835:Body Weight; D056486:Chemical and Drug Induced Liver Injury; D004731:Endotoxins / Q000097:blood; D004958:Estradiol / Q000097:blood; D000431:Ethanol / Q000008:administration & dosage / Q000652:urine; D005260:Female; D007728:Kupffer Cells / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000502:physiology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000473:pathology / Q000652:urine; D008297:Male; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012727:Sex Characteristics; D000637:Transaminases / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology
chemical_list: D004731:Endotoxins; D018950:Lipopolysaccharide Receptors; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D004958:Estradiol; D000637:Transaminases