title: Human neutrophil peptide-1 promotes alcohol-induced hepatic fibrosis and hepatocyte apoptosis.
abstract: OBJECTIVE
  Neutrophil infiltration of the liver is a typical feature of alcoholic liver injury. Human neutrophil peptide (HNP)-1 is an antimicrobial peptide secreted by neutrophils. The aim of this study was to determine if HNP-1 affects ethanol-induced liver injury and to examine the mechanism of liver injury induced by HNP-1.
  
  
  METHODS
  Transgenic (TG) mice expressing HNP-1 under the control of a β-actin-based promoter were established. Ethanol was orally administered to HNP-1 TG or wild-type C57BL/6N (WT) mice. SK-Hep1 hepatocellular carcinoma cells were used to investigate the effect of HNP-1 on hepatocytes in vitro.
  
  
  RESULTS
  After 24 weeks of ethanol intake, hepatic fibrosis and hepatocyte apoptosis were significantly more severe in TG mice than in WT mice. Levels of CD14, TLR4, and IL-6 in liver tissues were higher in TG mice than in WT mice. Apoptosis was accompanied by higher protein levels of caspase-3, caspase-8, and cleaved PARP in liver tissue. In addition, phosphorylated ASK1, ASK1, phosphorylated JNK, JNK1, JNK2, Bax, Bak and Bim were all more abundant in TG mice than in WT mice. In contrast, the level of anti-apoptotic Bcl2 in the liver was significantly lower in TG mice than in WT mice. Analysis of microRNAs in liver tissue showed that miR-34a-5p expression was significantly higher in TG mice than in WT mice. Furthermore, in the presence of ethanol, HNP-1 increased the apoptosis with the decreased level of Bcl2 in a concentration-dependent manner in vitro.
  
  
  CONCLUSIONS
  HNP-1 secreted by neutrophils may exacerbate alcohol-induced hepatic fibrosis and hepatocyte apoptosis with a decrease in Bcl2 expression and an increase in miR-34a-5p expression.
authors.affiliation: Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.|Department of International Island and Community Medicine, Kagoshima University Graduate School of Medical and Dental Science, Kagoshima, Japan.
authors.forename: Rie
authors.initials: R
authors.lastname: Ibusuki
authors.affiliation: Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.|Center for Digestive and Liver Diseases, Miyazaki Medical Center Hospital, Miyazaki, Japan.
authors.forename: Hirofumi
authors.identifier: http://orcid.org/0000-0002-6976-7483
authors.initials: H
authors.lastname: Uto
authors.affiliation: Department of HGF Tissue Repair and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Oda
authors.affiliation: Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Ohshige
authors.affiliation: Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Tabu
authors.affiliation: Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Seiichi
authors.initials: S
authors.lastname: Mawatari
authors.affiliation: Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Kumagai
authors.affiliation: Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Kanmura
authors.affiliation: Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Tamai
authors.affiliation: Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Moriuchi
authors.affiliation: Department of HGF Tissue Repair and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.|Kagoshima City Hospital, Kagoshima, Japan.
authors.forename: Hirohito
authors.initials: H
authors.lastname: Tsubouchi
authors.affiliation: Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.|Department of HGF Tissue Repair and Regenerative Medicine, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Ido
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress; D000431:Ethanol / Q000633:toxicity*; D022781:Hepatocytes / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008104:Liver Cirrhosis, Alcoholic; D008297:Male; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D023084:alpha-Defensins / Q000502:physiology*
chemical_list: C000595707:BCL2 protein, human; C522425:MIRN34 microRNA, human; D035683:MicroRNAs; D019253:Proto-Oncogene Proteins c-bcl-2; D023084:alpha-Defensins; C406413:human neutrophil peptide 1; D000431:Ethanol