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In this study we further investigate the pathology and potential mediators for the mortality in infected animals.<jats:italic>T. cruzi<\/jats:italic>-infected IL-10<jats:sup>\u2212\/\u2212<\/jats:sup>mice showed reduced parasitemia accompanied by increased systemic release of gamma interferon (IFN-\u03b3), IL-12, and reactive nitrogen intermediates and overproduction of tumor necrosis factor alpha (TNF-\u03b1). Despite this early resistance, IL-10<jats:sup>\u2212\/\u2212<\/jats:sup>mice died within the third week of infection, whereas all control mice survived acute infection. The clinical manifestation with weight loss, hypothermia, hypoglycemia, hyperkalemia, and increased liver-derived enzymes in the blood together with hepatic necrosis and intravascular coagulation in moribund mice indicated a toxic shock-like syndrome, possibly mediated by the systemic TNF-\u03b1 overproduction. Indeed, high production of systemic TNF-\u03b1 significantly correlated with mortality, and moribund mice died with critically high TNF-\u03b1 concentrations in the blood. Consequent treatment with anti-TNF-\u03b1 antiserum attenuated pathological changes in<jats:italic>T. cruzi<\/jats:italic>-infected IL-10<jats:sup>\u2212\/\u2212<\/jats:sup>mice and significantly prolonged survival; the mice died during the fourth week postinfection, again with a striking correlation between regaining high systemic TNF-\u03b1 concentrations and the time of death. Since elevated serum IL-12 and IFN-\u03b3 concentrations were not affected by the administration of antiserum, these studies suggest that TNF-\u03b1 is the direct mediator of this toxic shock syndrome. In conclusion, induction of endogenous IL-10 during experimentally induced Chagas' disease seems to be crucial for counterregulating an overshooting proinflammatory cytokine response resulting in TNF-\u03b1-mediated toxic shock.<\/jats:p>","DOI":"10.1128\/iai.68.7.4075-4083.2000","type":"journal-article","created":{"date-parts":[[2002,7,27]],"date-time":"2002-07-27T09:58:18Z","timestamp":1027763898000},"page":"4075-4083","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":113,"title":["Tumor Necrosis Factor Alpha-Mediated Toxic Shock in<i>Trypanosoma cruzi<\/i>-Infected Interleukin 10-Deficient Mice"],"prefix":"10.1128","volume":"68","author":[{"given":"Christoph","family":"Ho\u0308lscher","sequence":"first","affiliation":[{"name":"<!--label omitted: 1-->Max-Planck-Institute for Immunobiology1 and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Mohrs","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Max-Planck-Institute for Immunobiology1 and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen Juan","family":"Dai","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Max-Planck-Institute for Immunobiology1 and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriele","family":"Ko\u0308hler","sequence":"additional","affiliation":[{"name":"<!--label omitted: 2-->Department of Pathology, University of Freiburg,2Freiburg, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhard","family":"Ryffel","sequence":"additional","affiliation":[{"name":"<!--label omitted: 3-->Department of Immunology, University of Cape Town, Cape Town, South Africa3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gu\u0308nter A.","family":"Schaub","sequence":"additional","affiliation":[{"name":"<!--label omitted: 4-->Department of Special Zoology and Parasitology, University of Bochum, Bochum,4Germany, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Horst","family":"Mossmann","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Max-Planck-Institute for Immunobiology1 and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frank","family":"Brombacher","sequence":"additional","affiliation":[{"name":"<!--label omitted: 3-->Department of Immunology, University of Cape Town, Cape Town, South Africa3"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1006\/expr.1996.0109"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.55.7.1622-1625.1987"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118290"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1097\/00003246-199310001-00003"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.174.6.1549"},{"key":"e_1_3_2_7_2","unstructured":"Brandzaeg P. 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