title: CD1d-restricted natural killer T cells contribute to hepatic inflammation and fibrogenesis in mice.
abstract: OBJECTIVE
  Several lines of evidence suggest that innate immunity plays a key role in hepatic fibrogenesis. To clarify the role of natural killer (NK) T cells in hepatic inflammation and fibrogenesis, we here investigated xenobiotics-induced liver injury and subsequent fibrogenesis in mice lacking mature NKT cells caused by genetic disruption of the CD1d molecule.
  
  
  METHODS
  Male CD1d-knockout (KO) and wild-type (WT) mice were given repeated intraperitoneal injections of thioacetamide (TAA, 3times/week; 0.1-0.2mg/g BW) for up to 9 weeks, or a single intraperitoneal injection of CCl(4) (1 μl/g). Liver histology was evaluated, and expression levels of cytokines and matrix-related genes in the liver were quantitatively measured by real-time reverse transcription-polymerase chain reaction (RT-PCR).
  
  
  RESULTS
  Mortality following repeated injections of TAA was prevented almost completely in CD1d-KO mice. TAA-induced inflammatory responses and hepatocellular damage were markedly ameliorated in CD1d-KO mice. TAA-induced expression of smooth muscle α-actin (SMA) and transforming growth factor (TGF)β1 mRNA in the liver were also prevented largely in CD1d-KO mice. In fact, CD1d-KO mice developed minimal hepatic fibrosis after 9-weeks of administration of TAA, which caused overt bridging fibrosis in WT mice. Indeed, TAA-induced increases in α1(I)procollagen (COL1A1) and tissue inhibitor of matrix metalloproteinase (TIMP)-1 mRNA were blunted significantly in CD1d-KO mice. Similarly, acute CCl(4)-induced hepatic injury and subsequent profibrogenic responses were also reduced significantly in CD1d-KO mice.
  
  
  CONCLUSIONS
  These findings clearly indicated that CD1d-restricted NKT cells contribute to xenobiotics-induced hepatic inflammation, hepatocellular damage, and subsequent profibrogenic responses in the liver.
authors.affiliation: Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Ishikawa
authors.forename: Kenichi
authors.initials: K
authors.lastname: Ikejima
authors.forename: Hisafumi
authors.initials: H
authors.lastname: Yamagata
authors.forename: Tomonori
authors.initials: T
authors.lastname: Aoyama
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Kon
authors.forename: Kumiko
authors.initials: K
authors.lastname: Arai
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Takeda
authors.forename: Sumio
authors.initials: S
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D055610:Antigens, CD1d / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D016923:Cell Death / Q000187:drug effects / Q000276:immunology; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D024042:Collagen Type I / Q000235:genetics; D000090602:Collagen Type I, alpha 1 Chain; D022781:Hepatocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D007113:Immunity, Innate; D008103:Liver Cirrhosis / Q000209:etiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013853:Thioacetamide / Q000633:toxicity; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics
chemical_list: D055610:Antigens, CD1d; C526879:Cd1d1 protein, mouse; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; D012333:RNA, Messenger; D019715:Tissue Inhibitor of Metalloproteinase-1; D013853:Thioacetamide