{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T03:49:55Z","timestamp":1791258595257,"version":"4.1.0"},"reference-count":44,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2007,2,1]],"date-time":"2007-02-01T00:00:00Z","timestamp":1170288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2007,2,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Ab binding to CD20 has been shown to induce apoptosis in B cells. In this study, we demonstrate that rituximab sensitizes lymphoma B cells to Fas-induced apoptosis in a caspase-8-dependent manner. To elucidate the mechanism by which Rituximab affects Fas-mediated cell death, we investigated rituximab-induced signaling and apoptosis pathways. Rituximab-induced apoptosis involved the death receptor pathway and proceeded in a caspase-8-dependent manner. Ectopic overexpression of FLIP (the physiological inhibitor of the death receptor pathway) or application of zIETD-fmk (specific inhibitor of caspase-8, the initiator-caspase of the death receptor pathway) both specifically reduced rituximab-induced apoptosis in Ramos B cells. Blocking the death receptor ligands Fas ligand or TRAIL, using neutralizing Abs, did not inhibit apoptosis, implying that a direct death receptor\/ligand interaction is not involved in CD20-mediated cell death. Instead, we hypothesized that rituximab-induced apoptosis involves membrane clustering of Fas molecules that leads to formation of the death-inducing signaling complex (DISC) and downstream activation of the death receptor pathway. Indeed, Fas coimmune precipitation experiments showed that, upon CD20-cross-linking, Fas-associated death domain protein (FADD) and caspase-8 were recruited into the DISC. Additionally, rituximab induced CD20 and Fas translocation to raft-like domains on the cell surface. Further analysis revealed that, upon stimulation with rituximab, Fas, caspase-8, and FADD were found in sucrose-gradient raft fractions together with CD20. In conclusion, in this study, we present evidence for the involvement of the death receptor pathway in rituximab-induced apoptosis of Ramos B cells with concomitant sensitization of these cells to Fas-mediated apoptosis via Fas multimerization and recruitment of caspase-8 and FADD to the DISC.<\/jats:p>","DOI":"10.4049\/jimmunol.178.4.2287","type":"journal-article","created":{"date-parts":[[2014,4,18]],"date-time":"2014-04-18T19:02:49Z","timestamp":1397847769000},"page":"2287-2295","source":"Crossref","is-referenced-by-count":81,"title":["Fas Receptor Clustering and Involvement of the Death Receptor Pathway in Rituximab-Mediated Apoptosis with Concomitant Sensitization of Lymphoma B Cells to Fas-Induced Apoptosis"],"prefix":"10.1093","volume":"178","author":[{"given":"Alja J","family":"Stel","sequence":"first","affiliation":[{"name":"University Medical Center Groningen, Department of Pathology and Laboratory Medicine, Section Medical Biology\u2013Laboratory Tumor Immunology , Groningen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bram","family":"ten Cate","sequence":"additional","affiliation":[{"name":"University Medical Center Groningen, Department of Pathology and Laboratory Medicine, Section Medical Biology\u2013Laboratory Tumor Immunology , Groningen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan","family":"Jacobs","sequence":"additional","affiliation":[{"name":"University Medical Center Groningen, Department of Pathology and Laboratory Medicine, Section Medical Biology\u2013Laboratory Tumor Immunology , Groningen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan Willem","family":"Kok","sequence":"additional","affiliation":[{"name":"Department of Membrane Cell Biology, University Medical Center Groningen , Groningen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana C J","family":"Spierings","sequence":"additional","affiliation":[{"name":"Department of Immunology, St. Jude Children\u2019s Research Hospital , Memphis, TN 38105"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Dondorff","sequence":"additional","affiliation":[{"name":"University Medical Center Groningen, Department of Pathology and Laboratory Medicine, Section Medical Biology\u2013Laboratory Tumor Immunology , Groningen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wijnand","family":"Helfrich","sequence":"additional","affiliation":[{"name":"University Medical Center Groningen, Department of Pathology and Laboratory Medicine, Section Medical Biology\u2013Laboratory Tumor Immunology , Groningen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanneke C","family":"Kluin-Nelemans","sequence":"additional","affiliation":[{"name":"Department of Hematology, University Medical Center Groningen , Groningen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lou F M H","family":"de Leij","sequence":"additional","affiliation":[{"name":"University Medical Center Groningen, Department of Pathology and Laboratory Medicine, Section Medical Biology\u2013Laboratory Tumor Immunology , Groningen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sebo","family":"Withoff","sequence":"additional","affiliation":[{"name":"Department of Immunology, St. Jude Children\u2019s Research Hospital , Memphis, TN 38105"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart Jan","family":"Kroesen","sequence":"additional","affiliation":[{"name":"University Medical Center Groningen, Department of Pathology and Laboratory Medicine, Section Medical Biology\u2013Laboratory Tumor Immunology , Groningen ,","place":["The Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2007,2,15]]},"reference":[{"key":"2026012811140585400_R1","first-page":"55","volume-title":"Cell. Immunol.","year":"2000"},{"key":"2026012811140585400_R2","first-page":"1581","volume-title":"J. Immunol.","year":"2003"},{"key":"2026012811140585400_R3","first-page":"673","volume-title":"Cancer Immunol. Immunother.","year":"2000"},{"key":"2026012811140585400_R4","first-page":"1038","volume-title":"Blood","year":"2002"},{"key":"2026012811140585400_R5","first-page":"264","volume-title":"Cancer Res.","year":"2005"},{"key":"2026012811140585400_R6","first-page":"5137","volume-title":"Cancer Res.","year":"2001"},{"key":"2026012811140585400_R7","first-page":"2174","volume-title":"J. Immunol.","year":"2005"},{"key":"2026012811140585400_R8","first-page":"235","volume-title":"N. Engl. J. Med.","year":"2002"},{"key":"2026012811140585400_R9","first-page":"3725","volume-title":"Blood","year":"2005"},{"key":"2026012811140585400_R10","first-page":"133","volume-title":"Blood Cells Mol. Dis.","year":"2000"},{"key":"2026012811140585400_R11","first-page":"4494","volume-title":"J. Immunol.","year":"1993"},{"key":"2026012811140585400_R12","first-page":"7170","volume-title":"Cancer Res.","year":"2000"},{"key":"2026012811140585400_R13","first-page":"1183","volume-title":"Mol. Cancer Ther.","year":"2003"},{"key":"2026012811140585400_R14","first-page":"709","volume-title":"Clin. Cancer Res.","year":"2001"},{"key":"2026012811140585400_R15","first-page":"3530","volume-title":"Oncogene","year":"2004"},{"key":"2026012811140585400_R16","first-page":"7117","volume-title":"Cancer Res.","year":"2004"},{"key":"2026012811140585400_R17","first-page":"33","volume-title":"Haematologica","year":"2002"},{"key":"2026012811140585400_R18","first-page":"439","volume-title":"Clin. Exp. Immunol.","year":"2005"},{"key":"2026012811140585400_R19","first-page":"26953","volume-title":"J. Biol. Chem.","year":"1997"},{"key":"2026012811140585400_R20","first-page":"1405","volume-title":"Hum. Gene Ther.","year":"1996"},{"key":"2026012811140585400_R21","first-page":"14723","volume-title":"J. Biol. Chem.","year":"2003"},{"key":"2026012811140585400_R22","first-page":"271","volume-title":"J. Immunol. Methods","year":"1991"},{"key":"2026012811140585400_R23","first-page":"921","volume-title":"J. Histochem. Cytochem.","year":"1978"},{"key":"2026012811140585400_R24","first-page":"248","volume-title":"Anal. Biochem.","year":"1976"},{"key":"2026012811140585400_R25","first-page":"836","volume-title":"Clin. Cancer Res.","year":"2002"},{"key":"2026012811140585400_R26","first-page":"8114","volume-title":"Oncogene","year":"2005"},{"key":"2026012811140585400_R27","first-page":"32221","volume-title":"J. Biol. Chem.","year":"1997"},{"key":"2026012811140585400_R28","first-page":"281","volume-title":"Int. J. Cancer","year":"2004"},{"key":"2026012811140585400_R29","first-page":"447","volume-title":"J. Exp. Med.","year":"2001"},{"key":"2026012811140585400_R30","first-page":"207","volume-title":"Mol. Cell. Biol.","year":"2002"},{"key":"2026012811140585400_R31","first-page":"20589","volume-title":"J. Biol. Chem.","year":"2001"},{"key":"2026012811140585400_R32","first-page":"876","volume-title":"Biochem. Biophys. Res. Commun.","year":"2002"},{"key":"2026012811140585400_R33","first-page":"281","volume-title":"J. Cell Biol.","year":"1999"},{"key":"2026012811140585400_R34","first-page":"2316","volume-title":"J. Immunol.","year":"2004"},{"key":"2026012811140585400_R35","first-page":"31733","volume-title":"J. Biol. Chem.","year":"2000"},{"key":"2026012811140585400_R36","first-page":"998","volume-title":"EMBO J.","year":"2001"},{"key":"2026012811140585400_R37","first-page":"344","volume-title":"J. Biol. Chem.","year":"1998"},{"key":"2026012811140585400_R38","first-page":"534","volume-title":"Cancer Res.","year":"2003"},{"key":"2026012811140585400_R39","first-page":"3242","volume-title":"J. Immunol.","year":"1998"},{"key":"2026012811140585400_R40","first-page":"1164","volume-title":"Leukemia","year":"2003"},{"key":"2026012811140585400_R41","first-page":"1735","volume-title":"Leukemia","year":"2002"},{"key":"2026012811140585400_R42","first-page":"491","volume-title":"Cell","year":"1998"},{"key":"2026012811140585400_R43","first-page":"7987","volume-title":"J. Biol. Chem.","year":"1999"},{"key":"2026012811140585400_R44","first-page":"447","volume-title":"J. Exp. Med.","year":"2001"}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/178\/4\/2287\/62657938\/zim00407002287.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/178\/4\/2287\/62657938\/zim00407002287.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T16:14:13Z","timestamp":1769616853000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/178\/4\/2287\/8059456"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,2]]},"references-count":44,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2007,2,15]]},"published-print":{"date-parts":[[2007,2,15]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.178.4.2287","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2007,2]]},"published":{"date-parts":[[2007,2]]}}}