{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T20:28:40Z","timestamp":1791664120710,"version":"4.3.4"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","license":[{"start":{"date-parts":[[2017,9,26]],"date-time":"2017-09-26T00:00:00Z","timestamp":1506384000000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Hepatology Communications"],"published-print":{"date-parts":[[2017,11]]},"abstract":"<jats:p>The pathogenesis of primary sclerosing cholangitis (PSC) and the mechanistic link to inflammatory bowel disease remain ill\u2010defined. Ectonucleoside triphosphate diphosphohydrolase\u20101 (ENTPD1)\/clusters of differentiation (CD) 39, the dominant purinergic ecto\u2010enzyme, modulates intestinal inflammation. Here, we have explored the role of CD39 in biliary injury and fibrosis. The impact of CD39 deletion on disease severity was studied in multidrug resistance protein 2 (Mdr2)\u2013\/\u2013 and 3,5\u2010diethoxycarbonyl\u20101,4\u2010dihydrocollidine mouse models of sclerosing cholangitis and biliary fibrosis. Antibody\u2010mediated CD8+ T\u2010cell depletion, selective gut decontamination, experimental colitis, and administration of stable adenosine triphosphate (ATP) agonist were performed. Retinoic acid\u2010induced gut imprinting on T cells was studied<jats:italic toggle=\"yes\">in vitro<\/jats:italic>. Over half of Mdr2\u2013\/\u2013;CD39\u2013\/\u2013 double mutants, expected by Mendelian genetics, died<jats:italic toggle=\"yes\">in utero<\/jats:italic>. Compared to Mdr2\u2013\/\u2013;CD39+\/+, surviving Mdr2\u2013\/\u2013;CD39\u2013\/\u2013 mice demonstrated exacerbated liver injury, fibrosis, and ductular reaction. CD39 deficiency led to a selective increase in hepatic CD8+ T cells and integrin \u03b14\u03b27, a T\u2010cell gut\u2010tropism receptor. CD8+ cell depletion in Mdr2\u2013\/\u2013;CD39\u2013\/\u2013 mice diminished hepatobiliary injury and fibrosis. Treatment with antibiotics attenuated, whereas dextran sulfate sodium\u2010induced colitis exacerbated, liver fibrosis in Mdr2\u2013\/\u2013 mice. Colonic administration of \u03b1\u03b2\u2010ATP into CD39\u2010sufficient Mdr2\u2013\/\u2013 mice triggered hepatic CD8+ cell influx and recapitulated the severe phenotype observed in Mdr2\u2013\/\u2013;CD39\u2013\/\u2013 mice.<jats:italic toggle=\"yes\">In vitro<\/jats:italic>, addition of ATP promoted the retinoic acid\u2010induced imprinting of gut\u2010homing integrin \u03b14\u03b27 on naive CD8+ cells. CD39 expression was relatively low in human normal or PSC livers but abundantly present on immune cells of the colon and further up\u2010regulated in samples of patients with inflammatory bowel disease.<jats:italic toggle=\"yes\">Conclusion<\/jats:italic>: CD39 deletion promotes biliary injury and fibrosis through gut\u2010imprinted CD8+ T cells. Pharmacological modulation of purinergic signaling may represent a promising approach for the treatment of PSC. (<jats:italic toggle=\"yes\">Hepatology Communications<\/jats:italic>2017;1:957\u2013972)<\/jats:p>","DOI":"10.1002\/hep4.1084","type":"journal-article","created":{"date-parts":[[2017,9,26]],"date-time":"2017-09-26T15:22:11Z","timestamp":1506439331000},"page":"957-972","source":"Crossref","is-referenced-by-count":39,"title":["The ectonucleotidase ENTPD1\/CD39 limits biliary injury and fibrosis in mouse models of sclerosing cholangitis"],"prefix":"10.1097","volume":"1","author":[{"given":"Zhen\u2010Wei","family":"Peng","sequence":"first","affiliation":[{"name":"Department of Oncology,First Affiliated Hospital of Sun Yat\u2010sen University,Guangzhou,China"},{"name":"Division of Gastroenterology and Hepatology,Beth Israel Deaconess Medical Center, Harvard Medical School,Boston,MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja","family":"Rothweiler","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Beth Israel Deaconess Medical Center, Harvard Medical School,Boston,MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangyan","family":"Wei","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Beth Israel Deaconess Medical Center, Harvard Medical School,Boston,MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Ikenaga","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Beth Israel Deaconess Medical Center, Harvard Medical School,Boston,MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan B.","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Beth Israel Deaconess Medical Center, Harvard Medical School,Boston,MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deanna Y.","family":"Sverdlov","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Beth Israel Deaconess Medical Center, Harvard Medical School,Boston,MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kahini A.","family":"Vaid","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Beth Israel Deaconess Medical Center, Harvard Medical School,Boston,MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4510-1249","authenticated-orcid":false,"given":"Maria Serena","family":"Longhi","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology and Hepatology,Beth Israel Deaconess Medical Center, Harvard Medical School,Boston,MA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Kuang","sequence":"additional","affiliation":[{"name":"Department of Oncology,First Affiliated Hospital of Sun Yat\u2010sen University,Guangzhou,China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon 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