Zinc deprivation mediates alcohol-induced hepatocyte IL-8 analog expression in rodents via an epigenetic mechanism

Yantao Zhao, Wei Zhong, Xiuhua Sun, Zhenyuan Song, Dahn L. Clemens, Y. James Kang, Craig J. McClain, Zhanxiang Zhou

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Neutrophil infiltration caused by IL-8 production is a central mechanism in alcohol-induced hepatitis. This study was performed to examine if an epigenetic mechanism is involved in alcohol-induced IL-8 production. Mice were pair-fed an alcohol-containing liquid diet for 4 weeks. Alcohol exposure induced hepatitis as indicated by increased expression of keratinocyte-derived cytokine (mouse IL-8) and neutrophil infiltration. Alcohol exposure induced histone 3 hyperacetylation owing to inhibition of histone deacetylase (HDAC) in association with NF-κB activation. Cell culture studies showed that alcohol exposure induced IL-8 and cytokine-induced neutrophil chemoattractant-1 (CINC-1, rat IL-8) production in human VL-17A cells and rat H4IIEC3 cells, respectively, dependent on acetaldehyde production, oxidative stress, and zinc release. Zinc deprivation alone induced CINC-1 production and acted synergistically with lipopolysaccharide or tumor necrosis factor-α on CINC-1 production. Zinc deprivation induced histone 3 hyperacetylation at lysine 9 through suppression of HDAC activity. Zinc deprivation caused nuclear translocation of NF-κB, and reduced HDAC binding to NF-κB. Chromatin immunoprecipitation (ChIP) showed that zinc deprivation caused histone 3 hyperacetylation as well as increased NF-κB binding to the CINC-1 promoter. In conclusion, inactivation of HDAC caused by zinc deprivation is a novel mechanism underlying IL-8 up-regulation in alcoholic hepatitis.

Original languageEnglish (US)
Pages (from-to)693-702
Number of pages10
JournalAmerican Journal of Pathology
Volume179
Issue number2
DOIs
StatePublished - Aug 2011

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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