{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T10:12:44Z","timestamp":1789985564628,"version":"4.0.1"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2016,12]]},"abstract":"<jats:p>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\u2010related liver disease is a major cause of death in patients with CF. CFTR dysfunction affects innate immune pathways, generating a para\u2010inflammatory status in the liver and other epithelia. This study investigates the mechanisms linking CFTR to toll\u2010like 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\u2010defective cholangiocytes, Src tyrosine kinase self\u2010activates and phosphorylates toll\u2010like receptor 4, resulting in activation of nuclear factor kappa\u2010light\u2010chain\u2010enhancer of activated B cells and increased proinflammatory cytokine production in response to endotoxins. This Src\/nuclear factor kappa\u2010light\u2010chain\u2010enhancer of activated B cells\u2010dependent 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 <jats:italic toggle=\"yes\">in vitro<\/jats:italic>, and significantly attenuated endotoxin\u2010induced biliary damage and inflammation <jats:italic toggle=\"yes\">in vivo<\/jats:italic> (Cftr knockout mice). <jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: These findings reveal a novel function of CFTR as a regulator of toll\u2010like receptor 4 responses and cell polarity in biliary epithelial cells; this mechanism is pathogenetic, as shown by the protective effects of Src inhibition <jats:italic toggle=\"yes\">in vivo<\/jats:italic>, and may be a novel therapeutic target in CF\u2010related liver disease and other inflammatory cholangiopathies. (H<jats:sc>epatology<\/jats:sc> 2016;64:2118\u20102134).<\/jats:p>","DOI":"10.1002\/hep.28817","type":"journal-article","created":{"date-parts":[[2016,9,15]],"date-time":"2016-09-15T13:44:05Z","timestamp":1473947045000},"page":"2118-2134","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":72,"title":["The cystic fibrosis transmembrane conductance regulator controls biliary epithelial inflammation and permeability by regulating Src tyrosine kinase activity"],"prefix":"10.1097","volume":"64","author":[{"given":"Romina","family":"Fiorotto","sequence":"first","affiliation":[{"name":"Section of Digestive Diseases, Liver Center,Yale University,New Haven,CT"},{"name":"International Center for Digestive Health,University of Milan\u2010Bicocca,Milan,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ambra","family":"Villani","sequence":"additional","affiliation":[{"name":"Section of Digestive Diseases, Liver Center,Yale University,New Haven,CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonis","family":"Kourtidis","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology,Mayo Clinic Comprehensive Cancer Center,Jacksonville,FL"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Scirpo","sequence":"additional","affiliation":[{"name":"Section of Digestive Diseases, Liver Center,Yale University,New Haven,CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariangela","family":"Amenduni","sequence":"additional","affiliation":[{"name":"Section of Digestive Diseases, Liver Center,Yale University,New Haven,CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Geibel","sequence":"additional","affiliation":[{"name":"Department of Surgery,Yale University,New Haven,CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimiliano","family":"Cadamuro","sequence":"additional","affiliation":[{"name":"International Center for Digestive Health,University of Milan\u2010Bicocca,Milan,Italy"},{"name":"Section of Digestive Diseases, Department of Medicine and Surgery,University of Milan\u2010Bicocca,Milan,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Spirli","sequence":"additional","affiliation":[{"name":"Section of Digestive Diseases, Liver Center,Yale University,New Haven,CT"},{"name":"International Center for Digestive Health,University of Milan\u2010Bicocca,Milan,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panos Z.","family":"Anastasiadis","sequence":"additional","affiliation":[{"name":"Department of Cancer Biology,Mayo Clinic Comprehensive Cancer 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