title: Epidermal growth factor protects the liver against alcohol-induced injury and sensitization to bacterial lipopolysaccharide.
abstract: BACKGROUND
  Whereas the role of proinflammatory cytokines in the pathogenesis of alcoholic liver disease has been at the forefront of investigation, a possible role for anti-inflammatory cytokines in this disease has received little attention. This study investigated (1) the hepatic protective effect of an anti-inflammatory cytokine, epidermal growth factor (EGF), against deleterious effects of alcohol and sensitization to bacterial lipopolysaccharide (LPS), and (2) the possible mechanisms that underlie such protection.
  
  
  METHODS
  Male C57BL/6 mice were fed a Lieber-DeCarli liquid diet that contained alcohol or an isocaloric replacement for 6 weeks. The animals then were treated daily with human EGF for 7 days (5 microg/mouse), after which they were injected with either LPS (1 mg/kg of body weight) or vehicle and killed 8 hr later. Blood and liver were analyzed for plasma aminotransferase activity, liver histology, liver apoptotic nuclei, mRNA of several cytokines (tumor necrosis factor [TNF]-alpha, interleukin [IL]-1beta, IL-6, and IL-10), apoptotic ligands (TRAIL), cytokine receptors (TNFRp55), pro- and antiapoptotic regulators/adaptors (Fas receptor, FasL, FADD, TRADD, RIP, Bak, Bax, Bcl-X, Bcl-2 and Bcl-w), and caspase-8.
  
  
  RESULTS
  Alcohol increased plasma aminotransferase activity and sensitized the liver to the effects of LPS, such as polymorphonuclear infiltration, occurrence of necrotic foci and microabscesses, and increased apoptosis. These changes were associated with elevated mRNA expression of proapoptotic regulators/adaptors. EGF either counteracted or markedly blunted most of these effects. EGF did not affect liver mRNA expression of TNF-alpha, IL-1beta, IL-6, and IL-10, which suggested that these cytokines were not involved in EGF protective effect. EGF protection was mediated by down-regulation of apoptosis through suppression of proapoptotic gene expression.
  
  
  CONCLUSIONS
  EGF protects the liver against both alcohol-induced liver damage and liver sensitization to bacterial LPS through down-regulation of apoptosis.
authors.affiliation: Division of Digestive Diseases, A. B. Chandler Medical Center, University of Kentucky, Lexington 40536, USA. ivdeac0@uky.edu
authors.forename: Ion V
authors.initials: IV
authors.lastname: Deaciuc
authors.forename: Nympha B
authors.initials: NB
authors.lastname: D'Souza
authors.forename: Ravshan
authors.initials: R
authors.lastname: Burikhanov
authors.forename: Eun Y
authors.initials: EY
authors.lastname: Lee
authors.forename: Corneliu N
authors.initials: CN
authors.lastname: Tarba
authors.forename: Craig J
authors.initials: CJ
authors.lastname: McClain
authors.forename: Willem J S
authors.initials: WJ
authors.lastname: de Villiers
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D016207:Cytokines / Q000096:biosynthesis; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004815:Epidermal Growth Factor / Q000494:pharmacology* / Q000627:therapeutic use; D000431:Ethanol / Q000633:toxicity*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D000431:Ethanol; D004815:Epidermal Growth Factor