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In a model of concanavalin A (Con A)\u2010induced, CD4<jats:sup>+<\/jats:sup> T cell\u2010dependent experimental hepatitis in mice, in which TNF is a central mediator of apoptotic and necrotic liver damage, we now provide evidence for an essential <jats:italic>in vivo<\/jats:italic> function of TNFR2 in this pathophysiological process. We demonstrate that a cooperation of TNFR1 and TNFR2 is required for hepatotoxicity as mice deficient of either receptor were resistant against Con A. A significant role of TNFR2 for Con A\u2010induced hepatitis is also shown by the enhanced sensitivity of transgenic mice overexpressing the human TNFR2. The ligand for cytotoxic signaling via both TNF receptors is the precursor of soluble TNF, <jats:italic>i.e.<\/jats:italic> transmembrane TNF. Indeed, transmembrane TNF is sufficient to mediate hepatic damage, as transgenic mice deficient in wild\u2010type soluble TNF but expressing a mutated nonsecretable form of TNF developed inflammatory liver disease.<\/jats:p>","DOI":"10.1002\/eji.1830271119","type":"journal-article","created":{"date-parts":[[2007,3,2]],"date-time":"2007-03-02T04:06:15Z","timestamp":1172808375000},"page":"2870-2875","source":"Crossref","is-referenced-by-count":148,"title":["<i>In vivo<\/i> evidence for a functional role of both tumor necrosis factor (TNF) receptors and transmembrane TNF in experimental hepatitis"],"prefix":"10.1002","volume":"27","author":[{"given":"Sabine","family":"K\u00fcsters","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gisa","family":"Tiegs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena","family":"Alexopoulou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manolis","family":"Pasparakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleni","family":"Douni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald","family":"K\u00fcnstle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Horst","family":"Bluethmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Albrecht","family":"Wendel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klaus","family":"Pfizenmaier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Kollias","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Grell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2005,12,6]]},"reference":[{"key":"e_1_2_1_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.3895437"},{"key":"e_1_2_1_3_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.iy.10.040192.002211"},{"key":"e_1_2_1_4_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.cb.09.110193.001533"},{"key":"e_1_2_1_5_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.immunol.14.1.397"},{"key":"e_1_2_1_6_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.175.1.91"},{"key":"e_1_2_1_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/0016-5085(95)90282-1"},{"key":"e_1_2_1_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/0016-5085(94)90604-1"},{"key":"e_1_2_1_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.76.11.5939"},{"key":"e_1_2_1_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.51.3.891-895.1986"},{"key":"e_1_2_1_11_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.165.3.657"},{"key":"e_1_2_1_12_2","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.140.9.2994"},{"key":"e_1_2_1_13_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-2952(89)90208-6"},{"key":"e_1_2_1_14_2","first-page":"1220","volume":"146","author":"Leist M.","year":"1995","journal-title":"Am. 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