{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T11:09:04Z","timestamp":1790420944122,"version":"4.1.0"},"reference-count":41,"publisher":"Rockefeller University Press","issue":"3","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2004,8,2]]},"abstract":"<jats:p>Tumor necrosis factor (TNF) is a potent cytokine exerting critical functions in the activation and regulation of immune and inflammatory responses. Due to its pleiotropic activities, the amplitude and duration of TNF function must be tightly regulated. One of the mechanisms that may have evolved to modulate TNF function is the proteolytic cleavage of its cell surface receptors. In humans, mutations affecting shedding of the p55TNF receptor (R) have been linked with the development of the TNFR-associated periodic syndromes, disorders characterized by recurrent fever attacks and localized inflammation. Here we show that knock-in mice expressing a mutated nonsheddable p55TNFR develop Toll-like receptor\u2013dependent innate immune hyperreactivity, which renders their immune system more efficient at controlling intracellular bacterial infections. Notably, gain of function for antibacterial host defenses ensues at the cost of disbalanced inflammatory reactions that lead to pathology. Mutant mice exhibit spontaneous hepatitis, enhanced susceptibility to endotoxic shock, exacerbated TNF-dependent arthritis, and experimental autoimmune encephalomyelitis. These results introduce a new concept for receptor shedding as a mechanism setting up thresholds of cytokine function to balance resistance and susceptibility to disease. Assessment of p55TNFR shedding may thus be of prognostic value in infectious, inflammatory, and autoimmune diseases.<\/jats:p>","DOI":"10.1084\/jem.20040435","type":"journal-article","created":{"date-parts":[[2004,8,2]],"date-time":"2004-08-02T17:14:06Z","timestamp":1091466846000},"page":"367-376","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":163,"title":["Tumor Necrosis Factor (TNF) Receptor Shedding Controls Thresholds of Innate Immune Activation That Balance Opposing TNF Functions in Infectious and Inflammatory Diseases"],"prefix":"10.1084","volume":"200","author":[{"given":"Sofia","family":"Xanthoulea","sequence":"first","affiliation":[{"name":"1Institute of Immunology, Biomedical Sciences Research Center \u201cAl. Fleming,\u201d Vari 166-72, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manolis","family":"Pasparakis","sequence":"additional","affiliation":[{"name":"2European Molecular Biology Laboratory, Mouse Biology Programme, Monterotondo 00016, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stavroula","family":"Kousteni","sequence":"additional","affiliation":[{"name":"3Division of Endocrinology and Metabolism, Center for Osteoporosis and Metabolic Bone Diseases, University of Arkansas for Medical Sciences, Little Rock, AR 72205"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cord","family":"Brakebusch","sequence":"additional","affiliation":[{"name":"4Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Wallach","sequence":"additional","affiliation":[{"name":"4Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Bauer","sequence":"additional","affiliation":[{"name":"5Brain Research Institute, University of Vienna, Wien A-1090, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans","family":"Lassmann","sequence":"additional","affiliation":[{"name":"5Brain Research Institute, University of Vienna, Wien A-1090, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Kollias","sequence":"additional","affiliation":[{"name":"1Institute of Immunology, Biomedical Sciences Research Center \u201cAl. Fleming,\u201d Vari 166-72, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2004,8,2]]},"reference":[{"key":"2023072512421884200_BIB1","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1016\/0092-8674(94)90372-7","volume":"76","year":"1994","journal-title":"Cell."},{"key":"2023072512421884200_BIB2","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1146\/annurev.immunol.17.1.331","volume":"17","year":"1999","journal-title":"Annu. Rev. Immunol."},{"key":"2023072512421884200_BIB3","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/sj.cdd.4401189","volume":"10","year":"2003","journal-title":"Cell Death Differ."},{"key":"2023072512421884200_BIB4","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1006\/cimm.2000.1636","volume":"201","year":"2000","journal-title":"Cell. Immunol."},{"key":"2023072512421884200_BIB5","doi-asserted-by":"crossref","first-page":"2155","DOI":"10.4049\/jimmunol.157.5.2155","volume":"157","year":"1996","journal-title":"J. Immunol."},{"key":"2023072512421884200_BIB6","doi-asserted-by":"crossref","first-page":"3427","DOI":"10.4049\/jimmunol.160.7.3427","volume":"160","year":"1998","journal-title":"J. Immunol."},{"key":"2023072512421884200_BIB7","doi-asserted-by":"crossref","first-page":"2960","DOI":"10.1128\/IAI.66.6.2960-2968.1998","volume":"66","year":"1998","journal-title":"Infect. Immun."},{"key":"2023072512421884200_BIB8","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1128\/IAI.67.2.595-601.1999","volume":"67","year":"1999","journal-title":"Infect. Immun."},{"key":"2023072512421884200_BIB9","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1111\/j.1600-065X.1999.tb01315.x","volume":"169","year":"1999","journal-title":"Immunol. Rev."},{"key":"2023072512421884200_BIB10","doi-asserted-by":"crossref","first-page":"798","DOI":"10.1038\/364798a0","volume":"364","year":"1993","journal-title":"Nature."},{"key":"2023072512421884200_BIB11","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1016\/0092-8674(93)90134-C","volume":"73","year":"1993","journal-title":"Cell."},{"key":"2023072512421884200_BIB12","doi-asserted-by":"crossref","first-page":"943","DOI":"10.4049\/jimmunol.160.2.943","volume":"160","year":"1998","journal-title":"J. Immunol."},{"key":"2023072512421884200_BIB13","doi-asserted-by":"crossref","first-page":"3869","DOI":"10.4049\/jimmunol.158.8.3869","volume":"158","year":"1997","journal-title":"J. Immunol."},{"key":"2023072512421884200_BIB14","first-page":"1","volume":"54","year":"1995","journal-title":"Eur. J. Haematol."},{"key":"2023072512421884200_BIB15","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/1043-4666(90)90048-X","volume":"2","year":"1990","journal-title":"Cytokine."},{"key":"2023072512421884200_BIB16","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/BF01489489","volume":"15","year":"1995","journal-title":"J. Clin. Immunol."},{"key":"2023072512421884200_BIB17","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.1172\/JCI114853","volume":"86","year":"1990","journal-title":"J. Clin. Invest."},{"key":"2023072512421884200_BIB18","doi-asserted-by":"crossref","first-page":"5070","DOI":"10.4049\/jimmunol.152.10.5070","volume":"152","year":"1994","journal-title":"J. Immunol."},{"key":"2023072512421884200_BIB19","doi-asserted-by":"crossref","first-page":"4036","DOI":"10.4049\/jimmunol.152.8.4036","volume":"152","year":"1994","journal-title":"J. Immunol."},{"key":"2023072512421884200_BIB20","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1084\/jem.172.2.599","volume":"172","year":"1990","journal-title":"J. Exp. Med."},{"key":"2023072512421884200_BIB21","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1016\/S1359-6101(96)00026-3","volume":"7","year":"1996","journal-title":"Cytokine Growth Factor Rev."},{"key":"2023072512421884200_BIB22","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1084\/jem.181.2.607","volume":"181","year":"1995","journal-title":"J. Exp. Med."},{"key":"2023072512421884200_BIB23","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1038\/361266a0","volume":"361","year":"1993","journal-title":"Nature."},{"key":"2023072512421884200_BIB24","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1016\/S0092-8674(00)80721-7","volume":"97","year":"1999","journal-title":"Cell."},{"key":"2023072512421884200_BIB25","doi-asserted-by":"crossref","first-page":"5198","DOI":"10.4049\/jimmunol.155.11.5198","volume":"155","year":"1995","journal-title":"J. Immunol."},{"key":"2023072512421884200_BIB26","doi-asserted-by":"crossref","first-page":"2830","DOI":"10.1073\/pnas.88.7.2830","volume":"88","year":"1991","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072512421884200_BIB27","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1126\/science.271.5253.1289","volume":"271","year":"1996","journal-title":"Science."},{"key":"2023072512421884200_BIB28","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1084\/jem.184.4.1397","volume":"184","year":"1996","journal-title":"J. Exp. Med."},{"key":"2023072512421884200_BIB29","doi-asserted-by":"crossref","first-page":"5554","DOI":"10.4049\/jimmunol.151.10.5554","volume":"151","year":"1993","journal-title":"J. Immunol."},{"key":"2023072512421884200_BIB30","doi-asserted-by":"crossref","first-page":"4025","DOI":"10.1002\/j.1460-2075.1991.tb04978.x","volume":"10","year":"1991","journal-title":"EMBO J."},{"key":"2023072512421884200_BIB31","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1093\/nar\/gkg031","volume":"31","year":"2003","journal-title":"Nucleic Acids Res."},{"key":"2023072512421884200_BIB32","doi-asserted-by":"crossref","first-page":"2386","DOI":"10.1002\/art.11169","volume":"48","year":"2003","journal-title":"Arthritis Rheum."},{"key":"2023072512421884200_BIB33","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1097\/00005792-200209000-00002","volume":"81","year":"2002","journal-title":"Medicine (Baltimore)."},{"key":"2023072512421884200_BIB34","doi-asserted-by":"crossref","first-page":"2351","DOI":"10.1126\/science.288.5475.2351","volume":"288","year":"2000","journal-title":"Science."},{"key":"2023072512421884200_BIB35","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1016\/S0952-7915(00)00124-2","volume":"12","year":"2000","journal-title":"Curr. Opin. Immunol."},{"key":"2023072512421884200_BIB36","doi-asserted-by":"crossref","first-page":"32488","DOI":"10.1016\/S0021-9258(18)31661-2","volume":"269","year":"1994","journal-title":"J. Biol. Chem."},{"key":"2023072512421884200_BIB37","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1038\/323445a0","volume":"323","year":"1986","journal-title":"Nature."},{"key":"2023072512421884200_BIB38","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1101\/gad.8.9.1030","volume":"8","year":"1994","journal-title":"Genes Dev."},{"key":"2023072512421884200_BIB39","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1038\/372560a0","volume":"372","year":"1994","journal-title":"Nature."},{"key":"2023072512421884200_BIB40","doi-asserted-by":"crossref","first-page":"3629","DOI":"10.1128\/iai.57.11.3629-3636.1989","volume":"57","year":"1989","journal-title":"Infect. Immun."},{"key":"2023072512421884200_BIB41","doi-asserted-by":"crossref","first-page":"1543","DOI":"10.1084\/jem.169.5.1543","volume":"169","year":"1989","journal-title":"J. Exp. Med."}],"container-title":["The Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/200\/3\/367\/1715045\/jem2003367.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/200\/3\/367\/1715045\/jem2003367.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T08:50:17Z","timestamp":1690275017000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/200\/3\/367\/46244\/Tumor-Necrosis-Factor-TNF-Receptor-Shedding"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2004,8,2]]},"references-count":41,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2004,8,2]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.20040435","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.1020548.232661","asserted-by":"object"}]},"ISSN":["1540-9538","0022-1007"],"issn-type":[{"value":"1540-9538","type":"electronic"},{"value":"0022-1007","type":"print"}],"subject":[],"published":{"date-parts":[[2004,8,2]]}}}