{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T20:09:31Z","timestamp":1780085371737,"version":"3.54.0"},"reference-count":27,"publisher":"American Society for Clinical Investigation","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,3,9]]},"abstract":"<jats:p>\n                    Biliary atresia is an obstructive cholangiopathy of infancy that progresses to end-stage cirrhosis. Although the pathogenesis of the disease is not completely understood, previous reports link TNF\u03b1 to apoptosis of the bile duct epithelium in the presence of IFN\u03b3. Here, we investigate if TNF\u03b1 signaling regulates pathogenic mechanisms of biliary atresia. First, we quantified the expression of\n                    <jats:italic>TNFA<\/jats:italic>\n                    and its receptors\n                    <jats:italic>TNFR1<\/jats:italic>\n                    and\n                    <jats:italic>TNFR2<\/jats:italic>\n                    in human livers and found an increased expression of the receptors at the time of diagnosis. In mechanistic experiments using a neonatal mouse model of rhesus rotavirus\u2013induced (RRV-induced) biliary atresia, the expression of the ligand and both receptors increased 6- to 8-fold in hepatic DCs and NK lymphocytes above controls. The activation of tissue NK cells by RRV-primed DCs was independent of TNF\u03b1-TNFR signaling. Once activated, the expression of TNF\u03b1 by NK cells induced lysis of 55% \u00b1 2% of bile duct epithelial cells, which was completely prevented by blocking TNF\u03b1 or TNFR2, but not TNFR1. More notably, antibody-mediated or genetic disruption of TNF\u03b1-TNFR2 signaling in vivo decreased apoptosis and epithelial injury; suppressed the infiltration of livers by T cells, DCs, and NK cells; prevented extrahepatic bile duct obstruction; and promoted long-term survival. These findings point to a key role for the TNF\u03b1\/TNFR2 axis on pathogenesis of experimental biliary atresia and identify new therapeutic targets to suppress the disease phenotype.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.88747","type":"journal-article","created":{"date-parts":[[2017,3,8]],"date-time":"2017-03-08T11:01:03Z","timestamp":1488970863000},"source":"Crossref","is-referenced-by-count":25,"title":["Preferential TNF\u03b1 signaling via TNFR2 regulates epithelial injury and duct obstruction in experimental biliary atresia"],"prefix":"10.1172","volume":"2","author":[{"given":"Pranavkumar","family":"Shivakumar","sequence":"first","affiliation":[{"name":"Cincinnati Children\u2019s Hospital Medical Center and the Department of Pediatrics of the University Of Cincinnati College of Medicine, Cincinnati, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuki","family":"Mizuochi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reena","family":"Mourya","sequence":"additional","affiliation":[{"name":"Cincinnati Children\u2019s Hospital Medical Center and the Department of Pediatrics of the University Of Cincinnati College of Medicine, Cincinnati, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sridevi","family":"Gutta","sequence":"additional","affiliation":[{"name":"Cincinnati Children\u2019s Hospital Medical Center and the Department of Pediatrics of the University Of Cincinnati College of Medicine, Cincinnati, Ohio, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Yang","sequence":"additional","affiliation":[{"name":"Cincinnati Children\u2019s 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