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, Yujian Kang, Craig J. McClain, Zhanxiang Zhou

Research output: Contribution to journalArticle

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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 1 2011
Externally publishedYes

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Interleukin-8
Epigenomics
Zinc
Hepatocytes
Rodentia
Histone Deacetylases
Alcohols
Histones
Neutrophil Infiltration
Hepatitis
Cytokines
Alcoholic Hepatitis
Acetaldehyde
Chromatin Immunoprecipitation
Chemotactic Factors
Keratinocytes
Lysine
Lipopolysaccharides
Oxidative Stress
Neutrophils

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

Zinc deprivation mediates alcohol-induced hepatocyte IL-8 analog expression in rodents via an epigenetic mechanism. / Zhao, Yantao; Zhong, Wei; Sun, Xiuhua; Song, Zhenyuan; Clemens, Dahn L.; Kang, Yujian; McClain, Craig J.; Zhou, Zhanxiang.

In: American Journal of Pathology, Vol. 179, No. 2, 01.08.2011, p. 693-702.

Research output: Contribution to journalArticle

Zhao, Yantao ; Zhong, Wei ; Sun, Xiuhua ; Song, Zhenyuan ; Clemens, Dahn L. ; Kang, Yujian ; McClain, Craig J. ; Zhou, Zhanxiang. / Zinc deprivation mediates alcohol-induced hepatocyte IL-8 analog expression in rodents via an epigenetic mechanism. In: American Journal of Pathology. 2011 ; Vol. 179, No. 2. pp. 693-702.
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