title: CD14 is associated with biliary stricture formation.
abstract: The pathogenesis of intrahepatic biliary stricture formation in patients with primary sclerosing cholangitis (PSC) or after liver transplantation (LTx) remains elusive. CD14 receptor signaling is a key mediator of the innate immune system; its common genetic variant is associated with alcoholic liver disease. PSC and LTx cohort patients and primary biliary cirrhosis (PBC) control patients were genotyped for the CD14 -260C>T (rs2569190) polymorphism, and genotypes were correlated with long-term clinical outcome. Biliary tissue, bile, and whole blood of PSC patients and healthy controls were screened for markers of the innate immune system and bacterial infection. In 121 PSC patients, the CD14 -260C>T genotype was associated with development of dominant bile duct strictures (P = 0.02). In 365 LTx patients, TT carriers (4.1%) were protected against the formation of nonanastomotic biliary strictures versus CC/CT patients (12.6%; P = 0.01). Chemokine ligand 8 (P = 0.04) and chemokine receptor 6 (P = 0.004) were up-regulated in biliary tissue of PSC patients with the TT versus the CC/CT genotype. Lipopolysaccharide whole-blood stimulation resulted in a significant change in interleukin (IL)-8 (P = 0.05) and IL-12p40 levels (P = 0.04) in healthy control subjects carrying the TT genotype. TT PSC patients were protected against Gram-negative bacterial biliary infection (TT: 0% vs.
  
  
  
  22.5%; P = 0.02). Serum-soluble CD14 levels correlated with the CD14 -260C>T genotype (P = 0.02), representing an independent risk indicator of survival in PSC patients (hazard ratio, 0.40; 95% confidence interval, 0.19-0.86; P =0.01).
  
  
  
  The function of the innate immune response by CD14 is crucial during biliary infection and stricture formation. The benefits of CD14 signaling modification should be addressed in future studies. (Hepatology 2016;64:843-852).
authors.affiliation: Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg, Germany.
authors.forename: Kilian
authors.initials: K
authors.lastname: Friedrich
authors.affiliation: Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: Smit
authors.affiliation: Department of Internal Medicine I, University Hospital of Heidelberg, Heidelberg, Germany.
authors.forename: Maik
authors.initials: M
authors.lastname: Brune
authors.affiliation: Heidelberg University Hospital, Institute for Immunology, Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Giese
authors.affiliation: Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Rupp
authors.affiliation: Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Wannhoff
authors.affiliation: Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Kloeters
authors.affiliation: Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Leopold
authors.affiliation: Liver Center Munich, Department of Medicine II, University of Munich (LMU), Munich, Germany.|Transplantation Center, University of Munich, Munich, Germany.
authors.forename: Gerald Ulrich
authors.initials: GU
authors.lastname: Denk
authors.affiliation: Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg, Germany.
authors.forename: Karl Heinz
authors.initials: KH
authors.lastname: Weiss
authors.affiliation: Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Stremmel
authors.affiliation: Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Sauer
authors.affiliation: Liver Center Munich, Department of Medicine II, University of Munich (LMU), Munich, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Hohenester
authors.affiliation: Heidelberg University Hospital, Institute for Pathology, Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.affiliation: Department of General, Visceral and Transplant Surgery, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schemmer
authors.affiliation: Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg, Germany.
authors.forename: Daniel Nils
authors.initials: DN
authors.lastname: Gotthardt
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D002761:Cholangitis / Q000235:genetics / Q000382:microbiology; D015209:Cholangitis, Sclerosing / Q000097:blood / Q000150:complications* / Q000401:mortality; D015331:Cohort Studies; D003251:Constriction, Pathologic / Q000097:blood / Q000209:etiology; D005260:Female; D020022:Genetic Predisposition to Disease; D005858:Germany / Q000453:epidemiology; D016905:Gram-Negative Bacterial Infections / Q000235:genetics; D006801:Humans; D007113:Immunity, Innate; D018950:Lipopolysaccharide Receptors / Q000097:blood / Q000235:genetics*; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications / Q000097:blood / Q000209:etiology*; D055815:Young Adult
chemical_list: D018950:Lipopolysaccharide Receptors