title: TLR4, TLR9, and NLRP3 in biliary epithelial cells of primary sclerosing cholangitis: relationship with clinical characteristics.
abstract: OBJECTIVE
  Inappropriate innate immune responses have been suggested to contribute to the pathogenesis of primary sclerosing cholangitis (PSC). We evaluated the associations of expressions of toll-like receptor (TLR) 4, TLR9, and nucleotide-binding oligomerization domain-containing protein (NOD)-like receptor family pyrin domain containing 3 (NLRP3) in the biliary epithelial cells (BECs) with clinical features of PSC patients.
  
  
  METHODS
  We retrospectively evaluated the expressions of TLR4, TLR9, and NLRP3 in the intrahepatic BECs by immunohistochemical staining in 21 PSC patients and 10 normal controls. In PSC, 17 patients underwent liver biopsy, and, in the other four patients, liver specimens were obtained at the time of liver transplantation.
  
  
  RESULTS
  TLR9 expressions in BECs were higher in PSC patients than in normal controls. TLR9 expressions were correlated with Ludwig fibrosis scores in PSC patients. TLR4 and NLRP3 expressions were similar between PSC patients and normal controls. Seventeen PSC patients undergoing liver biopsy were followed up during a median period of 55.7 months. Four reached to liver transplantation and four developed cholangiocarcinoma. Patients developing cholangiocarcinoma showed lower NLRP3 expressions than the others. Patients reaching to liver transplantation showed higher TLR9 expressions. Expression levels of TLR9 and NLRP3 were not correlated with liver biochemical tests and Mayo risk scores.
  
  
  CONCLUSIONS
  In PSC, excessive immune responses through TLR9 signaling may be associated with the disease progression. Insufficient immune response through NLRP3 signaling may be associated with the development of cholangiocarcinoma. Evaluation of TLR9 and NLRP3 expressions in BECs may be useful for predicting the prognosis as an auxiliary marker.
authors.affiliation: Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsushita
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Miyake
authors.forename: Akinobu
authors.initials: A
authors.lastname: Takaki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yasunaka
authors.forename: Kazuko
authors.initials: K
authors.lastname: Koike
authors.forename: Fusao
authors.initials: F
authors.lastname: Ikeda
authors.forename: Hidenori
authors.initials: H
authors.lastname: Shiraha
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nouso
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001650:Bile Duct Neoplasms / Q000235:genetics / Q000276:immunology; D001653:Bile Ducts, Intrahepatic; D001659:Biliary Tract / Q000166:cytology / Q000276:immunology; D002352:Carrier Proteins / Q000032:analysis* / Q000235:genetics*; D002648:Child; D018281:Cholangiocarcinoma / Q000235:genetics / Q000276:immunology; D015209:Cholangitis, Sclerosing / Q000235:genetics / Q000276:immunology*; D018450:Disease Progression; D004847:Epithelial Cells / Q000276:immunology*; D005260:Female; D015870:Gene Expression; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000276:immunology*; D007150:Immunohistochemistry; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D011237:Predictive Value of Tests; D011379:Prognosis; D012189:Retrospective Studies; D051197:Toll-Like Receptor 4 / Q000032:analysis* / Q000235:genetics*; D051217:Toll-Like Receptor 9 / Q000032:analysis* / Q000235:genetics*; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C495345:TLR4 protein, human; C495371:TLR9 protein, human; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9
keywords: biliary epithelial cell; cholangiocarcinoma; inflammasome; innate immunity; primary sclerosing cholangitis; toll-like receptor