title: Zinc deprivation mediates alcohol-induced hepatocyte IL-8 analog expression in rodents via an epigenetic mechanism.
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.
authors.affiliation: Department of Medicine, the University of Louisville, Louisville, Kentucky, USA.
authors.forename: Yantao
authors.initials: Y
authors.lastname: Zhao
authors.forename: Wei
authors.initials: W
authors.lastname: Zhong
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Sun
authors.forename: Zhenyuan
authors.initials: Z
authors.lastname: Song
authors.forename: Dahn L
authors.initials: DL
authors.lastname: Clemens
authors.forename: Y James
authors.initials: YJ
authors.lastname: Kang
authors.forename: Craig J
authors.initials: CJ
authors.lastname: McClain
authors.forename: Zhanxiang
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D000079:Acetaldehyde / Q000378:metabolism; D000438:Alcohols / Q000494:pharmacology*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D044127:Epigenesis, Genetic; D006519:Hepatitis, Alcoholic / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000378:metabolism; D051381:Rats; D015854:Up-Regulation; D015032:Zinc / Q000378:metabolism*
chemical_list: D000438:Alcohols; D016209:Interleukin-8; D000079:Acetaldehyde; D015032:Zinc