title: Interleukin-17A plays a pivotal role in cholestatic liver fibrosis in mice.
abstract: BACKGROUND
  It was recently reported that serum interleukin (IL)-17 levels increased in liver fibrosis associated with human alcoholic liver disease. However, the role of IL-17 in liver fibrosis has not yet been elucidated. Therefore, the aim of this study was to evaluate the role of IL-17 on cholestatic liver fibrosis.
  
  
  METHODS
  IL-17A knockout (KO) and wild-type (WT) mice were subjected to bile duct ligation. Animals were sacrificed at designated times, and serum and liver tissues were collected. The mRNA expression of hepatic fibrotic markers was assessed, and distribution of activated hepatic stellate cells (HSCs) was determined by immunohistochemical staining. In an in vitro study, Kupffer cells (KCs) and HSCs were isolated from WT mice. KCs were cultured with IL-17A or IL-17F, and production of tumor necrosis factor α (TNF-α) and transforming growth factor β1 (TGF-β1) was measured. HSCs were cultured with IL-17A or IL-17F, and morphologic changes were assessed by immunohistochemical staining.
  
  
  RESULTS
  Liver damage observed in the WT mice was significantly improved in the KO mice. Serum TNF-α and TGF-β1 levels were significantly decreased in the KO compared with the WT mice. The hepatic mRNA expression of TNF-α, TGF-β1, and collagen 1α1, which increased in the WT mice, also significantly decreased in the KO mice. Increased hepatic fibrosis in the WT mice was significantly improved in the KO mice. Cytokine production was increased in IL-17A-treated KCs. The most remarkable myofibroblast-like changes were observed in isolated HSCs in the presence of IL-17A.
  
  
  CONCLUSIONS
  IL-17A was involved in the pathogenesis of cholestatic liver fibrosis by activation of both the KCs and HSCs.
authors.affiliation: First Department of Surgery, University of Yamanashi, Yamanashi, Japan.
authors.forename: Michio
authors.initials: M
authors.lastname: Hara
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kono
authors.forename: Shinji
authors.initials: S
authors.lastname: Furuya
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Hirayama
authors.forename: Masato
authors.initials: M
authors.lastname: Tsuchiya
authors.forename: Hideki
authors.initials: H
authors.lastname: Fujii
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D004195:Disease Models, Animal; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006909:Hydroxyproline / Q000378:metabolism; D066298:In Vitro Techniques; D020381:Interleukin-17 / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000199:Actins; D024042:Collagen Type I; D020381:Interleukin-17; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; C544013:alpha-smooth muscle actin, mouse; D006909:Hydroxyproline
keywords: Bile duct ligation; Hepatic stellate cell; Interleukin-17A; Interleukin-17A knockout mouse; Kupffer cell