{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T14:26:52Z","timestamp":1783348012490,"version":"3.54.6"},"reference-count":47,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"1","license":[{"start":{"date-parts":[[2015,9,1]],"date-time":"2015-09-01T00:00:00Z","timestamp":1441065600000},"content-version":"tdm","delay-in-days":2800,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2008,1]]},"abstract":"<jats:sec>\n            <jats:title\/>\n            <jats:p>\n                                 <jats:bold>Transforming growth factor beta (TGF\u03b2) promotes hepatocellular apoptosis and suppresses hepatic lymphocyte responses in part through activation of Smad3. The purpose of the current study was to determine the importance of Smad3 signaling in an experimental model of autoimmune hepatitis induced by concanavalin A (ConA), a process involving T cell activation and hepatocellular apoptosis. C57Bl\/6 wild-type (Wt) or Smad3-deficient (Smad3\u2212\/\u2212) mice were injected intravenously with 15 mg\/kg ConA or vehicle. Nine hours post ConA injection, Wt mice presented with severe hepatitis as assessed by increased liver transferases. This injury was associated with eosinophil accumulation and preceded at 3 hours post-injection by significant increases in hepatic T helper 1 (interferon gamma) and T helper 2 (interleukin-4) cytokine production. Absence of Smad3 significantly blunted hepatocellular injury 9 hours post ConA injection, which was associated with reduced early T helper 1 and T helper 2 cytokine production and eosinophil accumulation. Smad3\u2212\/\u2212 livers also showed significant reductions in hepatocellular apoptosis as assessed by terminal UTP nick-end labeling when compared to ConA-treated Wt mice in conjunction with reduced caspase 3 cleavage, which was likely mediated by a Smad3-dependent inhibition of the survival factor extracellular signal-regulated kinase 1\/2.<\/jats:bold>\n                                 <jats:bold>\n                                    In vitro\n                                 <\/jats:bold>\n                                 <jats:bold>, Smad3\u2212\/\u2212 hepatocytes were resistant to TGF\u03b2-induced apoptosis, and this protection was dependent on extracellular signal-regulated kinase activation.<\/jats:bold>\n                                 <jats:bold>\n                                    Conclusion:\n                                 <\/jats:bold>\n                                 <jats:bold>Together, these results show, for the first time, the significance of Smad3 signaling in autoimmune hepatitis, underlining the control of Smad3-dependent TGF\u03b2 signaling on proinflammatory cytokine production, eosinophil recruitment, and hepatocellular apoptosis. Interruption of this pathway could be beneficial clinically to limit acute fulminant liver pathologies. (Hepatology 2007.)<\/jats:bold>\n                              <\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.21956","type":"journal-article","created":{"date-parts":[[2007,11,19]],"date-time":"2007-11-19T22:46:46Z","timestamp":1195512406000},"page":"113-126","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":21,"title":["Pivotal role of Smad3 in a mouse model of T cell\u2013mediated hepatitis"],"prefix":"10.1097","volume":"47","author":[{"given":"Michael","family":"Kremer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley W.","family":"Perry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard J.","family":"Milton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard 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