title: Toll-like receptor 7 agonist induces hypoplasia of the biliary system in a neonatal mouse model.
abstract: OBJECTIVE
  Viral infections and innate immunity signaling, especially Toll-like receptor 7 (TLR7) have been implicated in the pathogenesis of biliary atresia (BA). Administration of rhesus rotavirus-type A to newborn Balb/c mice produces inflammatory obstruction of bile ducts, which resembles human BA. However, whether activation of TLR7 signaling plays a role in neonatal hepatobiliary injury remains to be investigated.
  
  
  METHODS
  TLR7 agonist, imiquimod (R837), was intraperitoneally administered to Balb/c mice within 24 hours of birth and then every other day. Morphological and histological injuries of liver and gallbladder were examined at 2 weeks. Hepatic messenger RNA expression of TLR7 signaling was studied. Terminal deoxynucleotidyl transferase 2'-deoxyuridine 5'-triphosphate nick end labeling staining was used to delineate hepatobiliary apoptosis upon TLR7 stimulation.
  
  
  RESULTS
  TLR7 agonist, imiquimod, induced hypoplasia of the biliary system of neonatal Balb/c mice both in atrophic gallbladder and in paucity of intrahepatic bile ducts. There was significantly higher hepatic expression of TLR7 and downstream innate immunity-mediated interferon regulatory factor 7, interferon-α, and tumor necrosis factor-α. In addition, terminal deoxynucleotidyl transferase 2'-deoxyuridine 5'-triphosphate nick end labeling-positive cells in the liver were increased after injections of TLR7 agonist.
  
  
  CONCLUSIONS
  The results demonstrate that TLR7 activation may trigger innate immunity pathways and induce apoptosis and hypoplasia of neonatal biliary trees in Balb/c mice. The novel findings give an implication of pathogenesis of infantile cholestasis, such as BA.
authors: Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
authors: Ying-Hsien
authors: YH
authors: Huang
authors: Graduate Institute of Clinical Medicine Sciences, Chang Gung University College of Medicine, Taoyuan, Taiwan; Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Hsiang-Hung
authors: HH
authors: Shih
authors: Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
authors: Mao-Meng
authors: MM
authors: Tiao
authors: Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
authors: Chao-Cheng
authors: CC
authors: Huang
authors: Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
authors: Kuang-Che
authors: KC
authors: Kuo
authors: Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
authors: Fu-Chen
authors: FC
authors: Huang
authors: Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan.
authors: Ya-Ling
authors: YL
authors: Yang
authors: Graduate Institute of Clinical Medicine Sciences, Chang Gung University College of Medicine, Taoyuan, Taiwan; Department of Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. Electronic address: jhchuang@adm.cgmh.org.tw.
authors: Jiin-Haur
authors: JH
authors: Chuang
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001656:Biliary Atresia / Q000139:chemically induced / Q000473:pathology*; D001659:Biliary Tract / Q000473:pathology*; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D002779:Cholestasis / Q000473:pathology*; D004253:DNA Nucleotidylexotransferase / Q000235:genetics; D004195:Disease Models, Animal; D005704:Gallbladder / Q000473:pathology*; D000077271:Imiquimod; D050839:Interferon Regulatory Factor-7 / Q000378:metabolism; D016898:Interferon-alpha / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000096:biosynthesis; D012401:Rotavirus / Q000472:pathogenicity; D012400:Rotavirus Infections / Q000473:pathology; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000634:Aminoquinolines; D050839:Interferon Regulatory Factor-7; D016898:Interferon-alpha; C494235:Irf7 protein, mouse; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D014409:Tumor Necrosis Factor-alpha; D004253:DNA Nucleotidylexotransferase; D000077271:Imiquimod
keywords: Balb/c mice; animal model; biliary atresia; infantile cholestasis; innate immunity; toll-like receptor 7