Epidermal growth factor protects the liver against alcohol-induced injury and sensitization to bacterial lipopolysaccharide

Ion V. Deaciuc, Nympha B. D'Souza, Ravshan Burikhanov, Eun Y. Lee, Corneliu N. Tarba, Craig J. McClain, Willem J.S. De Villiers

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

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 μg/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]-α, interleukin [IL]-1β, 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 of markedly blunted most of these effects. EGF did not affect liver mRNA expression of TNF-α, IL-1β, 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.

Original languageEnglish
Pages (from-to)864-874
Number of pages11
JournalAlcoholism: Clinical and Experimental Research
Volume26
Issue number6
DOIs
StatePublished - 2002

Keywords

  • Apoptosis
  • Apoptotic regulators
  • Cytokines

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Toxicology
  • Psychiatry and Mental health

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