{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T10:25:21Z","timestamp":1789986321051,"version":"4.0.1"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2018,3,25]],"date-time":"2018-03-25T00:00:00Z","timestamp":1521936000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2018,3,25]],"date-time":"2018-03-25T00:00:00Z","timestamp":1521936000000},"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":[[2018,5]]},"abstract":"<jats:p>Congenital hepatic fibrosis (CHF), a genetic disease caused by mutations in the polycystic kidney and hepatic disease 1 (PKHD1) gene, encoding for the protein fibrocystin\/polyductin complex, is characterized by biliary dysgenesis, progressive portal fibrosis, and a protein kinase A\u2013mediated activating phosphorylation of \u03b2\u2010catenin at Ser675. Biliary structures of<jats:italic toggle=\"yes\">Pkhd1del4\/del4<\/jats:italic>mice, a mouse model of CHF, secrete chemokine (C\u2010X\u2010C motif) ligand 10 (CXCL10), a chemokine able to recruit macrophages. The aim of this study was to clarify whether CXCL10 plays a pathogenetic role in disease progression in CHF\/Caroli disease and to understand the mechanisms leading to increased CXCL10 secretion. We demonstrate that treatment of<jats:italic toggle=\"yes\">Pkhd1del4\/del4<\/jats:italic>mice for 3 months with AMG\u2010487, an inhibitor of CXC chemokine receptor family 3, the cognate receptor of CXCL10, reduces the peribiliary recruitment of alternative activated macrophages (cluster of differentiation 45<jats:sup>+<\/jats:sup>F4\/80<jats:sup>+<\/jats:sup>cells), spleen size, liver fibrosis (sirius red), and cyst growth (cytokeratin 19\u2013positive area), consistent with a pathogenetic role of CXCL10. Furthermore, we show that in fibrocystin\/polyductin complex\u2013defective cholangiocytes, isolated from<jats:italic toggle=\"yes\">Pkhd1del4\/del4<\/jats:italic>mice, CXCL10 production is mediated by Janus kinase\/signal transducer and activator of transcription 3 in response to interleukin 1beta (IL\u20101\u03b2) and \u03b2\u2010catenin. Specifically, IL\u20101\u03b2 promotes signal transducer and activator of transcription 3 phosphorylation, whereas \u03b2\u2010catenin promotes its nuclear translocation. Increased pro\u2010IL\u20101\u03b2 was regulated by nuclear factor kappa\u2010light\u2010chain\u2010enhancer of activated B cells, and increased secretion of active IL\u20101\u03b2 was mediated by the activation of Nod\u2010like receptors, pyrin domain containing 3 inflammasome (increased expression of caspase 1 and Nod\u2010like receptors, pyrin domain containing 3).<jats:italic toggle=\"yes\">Conclusion:<\/jats:italic>In fibrocystin\/polyductin complex\u2013defective cholangiocytes, \u03b2\u2010catenin and IL\u20101\u03b2 are responsible for signal transducer and activator of transcription 3\u2013dependent secretion of CXCL10;<jats:italic toggle=\"yes\">in vivo<\/jats:italic>experiments show that the CXCL10\/CXC chemokine receptor family 3 axis prevents the recruitment of macrophages, reduces inflammation, and halts the progression of the disease; the increased production of IL\u20101\u03b2 highlights the autoinflammatory nature of CHF and may open novel therapeutic avenues. (H<jats:sc>epatology<\/jats:sc>2018;67:1903\u20101919).<\/jats:p>","DOI":"10.1002\/hep.29652","type":"journal-article","created":{"date-parts":[[2017,11,15]],"date-time":"2017-11-15T15:42:47Z","timestamp":1510760567000},"page":"1903-1919","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":44,"title":["\u03b2\u2010Catenin and interleukin\u20101\u03b2\u2013dependent chemokine (C\u2010X\u2010C motif) ligand 10 production drives progression of disease in a mouse model of congenital hepatic fibrosis"],"prefix":"10.1097","volume":"67","author":[{"given":"Eleanna","family":"Kaffe","sequence":"first","affiliation":[{"name":"Section of Digestive Diseases, Liver Center,Yale University,New Haven,CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Romina","family":"Fiorotto","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":"Francesca","family":"Pellegrino","sequence":"additional","affiliation":[{"name":"Section of Digestive Diseases, Liver Center,Yale University,New Haven,CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Mariotti","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"},{"name":"Department of Molecular Medicine,University of Padua, School of Medicine,Padua,Italy"}],"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":"Massimiliano","family":"Cadamuro","sequence":"additional","affiliation":[{"name":"International Center for Digestive Health,University of Milan\u2010Bicocca,Milan,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Fabris","sequence":"additional","affiliation":[{"name":"International Center for Digestive Health,University of Milan\u2010Bicocca,Milan,Italy"},{"name":"Department of Molecular Medicine,University of Padua, School of Medicine,Padua,Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Strazzabosco","sequence":"additional","affiliation":[{"name":"Section of Digestive Diseases, Liver Center,Yale University,New Haven,CT"},{"name":"International Center for Digestive Health,University of 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