title: The cystic fibrosis transmembrane conductance regulator controls biliary epithelial inflammation and permeability by regulating Src tyrosine kinase activity.
abstract: In the liver, the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) regulates bile secretion and other functions at the apical membrane of biliary epithelial cells (i.e., cholangiocytes). CF-related liver disease is a major cause of death in patients with CF. CFTR dysfunction affects innate immune pathways, generating a para-inflammatory status in the liver and other epithelia. This study investigates the mechanisms linking CFTR to toll-like receptor 4 activity. We found that CFTR is associated with a multiprotein complex at the apical membrane of normal mouse cholangiocytes, with proteins that negatively control Rous sarcoma oncogene cellular homolog (Src) activity. In CFTR-defective cholangiocytes, Src tyrosine kinase self-activates and phosphorylates toll-like receptor 4, resulting in activation of nuclear factor kappa-light-chain-enhancer of activated B cells and increased proinflammatory cytokine production in response to endotoxins. This Src/nuclear factor kappa-light-chain-enhancer of activated B cells-dependent inflammatory process attracts inflammatory cells but also generates changes in the apical junctional complex and loss of epithelial barrier function. Inhibition of Src decreased the inflammatory response of CF cholangiocytes to lipopolysaccharide, rescued the junctional defect in vitro, and significantly attenuated endotoxin-induced biliary damage and inflammation in vivo (Cftr knockout mice).
  
  
  
  These findings reveal a novel function of CFTR as a regulator of toll-like receptor 4 responses and cell polarity in biliary epithelial cells; this mechanism is pathogenetic, as shown by the protective effects of Src inhibition in vivo, and may be a novel therapeutic target in CF-related liver disease and other inflammatory cholangiopathies. (Hepatology 2016;64:2118-2134).
authors.affiliation: Section of Digestive Diseases, Liver Center, Yale University, New Haven, CT.|International Center for Digestive Health, University of Milan-Bicocca, Milan, Italy.
authors.forename: Romina
authors.initials: R
authors.lastname: Fiorotto
authors.affiliation: Section of Digestive Diseases, Liver Center, Yale University, New Haven, CT.
authors.forename: Ambra
authors.initials: A
authors.lastname: Villani
authors.affiliation: Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, FL.
authors.forename: Antonis
authors.initials: A
authors.lastname: Kourtidis
authors.affiliation: Section of Digestive Diseases, Liver Center, Yale University, New Haven, CT.
authors.forename: Roberto
authors.initials: R
authors.lastname: Scirpo
authors.affiliation: Section of Digestive Diseases, Liver Center, Yale University, New Haven, CT.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Amenduni
authors.affiliation: Department of Surgery, Yale University, New Haven, CT.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Geibel
authors.affiliation: International Center for Digestive Health, University of Milan-Bicocca, Milan, Italy.|Section of Digestive Diseases, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy.
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Cadamuro
authors.affiliation: Section of Digestive Diseases, Liver Center, Yale University, New Haven, CT.|International Center for Digestive Health, University of Milan-Bicocca, Milan, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Spirli
authors.affiliation: Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, FL.
authors.forename: Panos Z
authors.initials: PZ
authors.lastname: Anastasiadis
authors.affiliation: Section of Digestive Diseases, Liver Center, Yale University, New Haven, CT.|International Center for Digestive Health, University of Milan-Bicocca, Milan, Italy.|Section of Digestive Diseases, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Strazzabosco
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000166:cytology / Q000201:enzymology; D002462:Cell Membrane; D002478:Cells, Cultured; D003550:Cystic Fibrosis; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000502:physiology*; D004848:Epithelium; D007249:Inflammation / Q000209:etiology*; D051379:Mice; D010539:Permeability; D051197:Toll-Like Receptor 4 / Q000502:physiology*; D019061:src-Family Kinases / Q000502:physiology*
chemical_list: D051197:Toll-Like Receptor 4; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D019061:src-Family Kinases