{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T13:13:27Z","timestamp":1788268407655,"version":"build-2803163510"},"reference-count":34,"publisher":"Wiley","issue":"13","license":[{"start":{"date-parts":[[2001,11,1]],"date-time":"2001-11-01T00:00:00Z","timestamp":1004572800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2001,11,1]],"date-time":"2001-11-01T00:00:00Z","timestamp":1004572800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["faseb.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The FASEB Journal"],"published-print":{"date-parts":[[2001,11]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Fas\u2010mediated mechanisms of apoptosis are thought to be involved in the bile duct loss that characterizes diseases such as primary biliary cirrhosis (PBC). We have previously shown that activation of CD40 on hepatocytes can amplify Fas\u2010mediated apoptosis; in the present study, we investigated interactions between CD40 and Fas in biliary epithelial cells (BEC). We report that the bile ducts in PBC liver tissue frequently express increased levels of Fas, Fas ligand (FasL), and CD40 associated with apoptotic BEC. The portal mononuclear infiltrate contains CD40L+ve T cells and macrophages, thereby demonstrating a potential mechanism for CD40 engagement in vivo. Primary cultures of human BEC also expressed Fas, FasL, and CD40 but not CD40L protein or mRNA. Activation of CD40 on BEC using recombinant CD40L increased transcriptional expression of FasL and induced apoptosis, which was inhibited by neutralizing antibodies to either Fas or FasL. Thus, CD40\u2010induced apoptosis of BEC is mediated through Fas\/FasL. We then investigated the intracellular signals and transcription factors activated in BEC and found that NF\u2010\u03baB and AP\u20101 were both activated after CD40 ligation. Increased functional NF\u2010\u03baB was seen early after CD40 ligation, but returned to baseline levels after 4 h. In contrast, the rapid up\u2010regulation of AP\u20101 was sustained over 24 h. This study provides further functional evidence of the ability of CD40 to induce Fas\/FasL\u2010dependent apoptosis of liver epithelial cells supporting the importance of cross\u2010talk between tumor necrosis factor (TNF) receptor family members as an amplification step in apoptosis induction. Sustained activation of AP\u20101 in the absence of NF\u2010\u03baB signaling may be a critical factor in determining the outcome of CD40 engagement.\u2014Afford, S. C., Ahmed\u2010Choudhury, J., Randhawa, S., Russell, C., Youster, J., Crosby, H. A., Eliopoulos, A., Hubscher, S. G., Young, L. S., Adams, D. H. CD40 activation\u2010induced, Fas\u2010dependent apoptosis and NFkB\/AP\u20101 signaling in human intrahepatic biliary epithelial cells.\n                    <jats:italic>FASEB J<\/jats:italic>\n                    . 15, 2345\u20102354 (2001)\n                  <\/jats:p>","DOI":"10.1096\/fj.01-0088com","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T19:03:24Z","timestamp":1027710204000},"page":"2345-2354","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":104,"title":["CD40 activation\u2010induced, Fas\u2010dependent apoptosis and NF\u2010\u03baB\/AP\u20101 signaling in human intrahepatic biliary epithelial cells"],"prefix":"10.1096","volume":"15","author":[{"given":"SIMON C.","family":"AFFORD","sequence":"first","affiliation":[{"name":"The Liver Research Laboratories MRC Centre for Immune Regulation Birmingham B15 2TH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JALAL","family":"AHMED-CHOUDHURY","sequence":"additional","affiliation":[{"name":"The Liver Research Laboratories MRC Centre for Immune Regulation Birmingham B15 2TH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"SATINDER","family":"RANDHAWA","sequence":"additional","affiliation":[{"name":"The Liver Research Laboratories MRC Centre for Immune Regulation Birmingham B15 2TH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"CLARE","family":"RUSSELL","sequence":"additional","affiliation":[{"name":"The Liver Research Laboratories MRC Centre for Immune Regulation Birmingham B15 2TH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"JANINE","family":"YOUSTER","sequence":"additional","affiliation":[{"name":"The Liver Research Laboratories MRC Centre for Immune Regulation Birmingham B15 2TH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"HEATHER A.","family":"CROSBY","sequence":"additional","affiliation":[{"name":"The Liver Research Laboratories MRC Centre for Immune Regulation Birmingham B15 2TH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"ARISTIDES","family":"ELIOPOULOS","sequence":"additional","affiliation":[{"name":"The CRC Institute for Cancer Studies Institute of Clinical Science Queen Elizabeth Hospital Birmingham B15 2TH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"STEFAN G.","family":"HUBSCHER","sequence":"additional","affiliation":[{"name":"The Department of Pathology The University of Birmingham Birmingham B15 2TH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"LAWRENCE S.","family":"YOUNG","sequence":"additional","affiliation":[{"name":"The CRC Institute for Cancer Studies Institute of Clinical Science Queen Elizabeth Hospital Birmingham B15 2TH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"DAVID H.","family":"ADAMS","sequence":"additional","affiliation":[{"name":"The Liver Research Laboratories MRC Centre for Immune Regulation Birmingham B15 2TH UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2001,11,1]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(87)91802-2"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/00007890-199105000-00014"},{"key":"e_1_2_6_4_1","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1002\/hep.510260604","article-title":"Enhanced apoptosis relates to bile duct loss in primary biliary cirrhosis","volume":"27","author":"Harada K.","year":"1997","journal-title":"Hepatology"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(95)90365-8"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1053\/he.2000.5764"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm0196-80"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/364806a0"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm0497-409"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm0598-588"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.182.5.1223"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.189.2.441"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0952-7915(97)80078-7"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/35393"},{"key":"e_1_2_6_15_1","first-page":"2243","article-title":"CD40-induced growth inhibition in epithelial cells is mimicked by Epstein-Barr Virus-encoded LMP1: involvement of TRAF3 as a common mediator","volume":"13","author":"Eliopoulos A. 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