{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T14:08:08Z","timestamp":1770732488563,"version":"3.49.0"},"reference-count":0,"publisher":"Rockefeller University Press","issue":"3","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[1995,3,1]]},"abstract":"<jats:p>Interleukin 12 (IL-12) doses in excess of 100 ng\/d have been shown to induce profound immunotoxicities in mice infected with lymphocytic choriomeningitis virus (LCMV). These immunotoxicities are characterized by almost complete inhibition of virus-induced CD8+ T cell expansion and CTL activation, and up to 2 log increases in viral replication. They are accompanied by induction of serum tumor necrosis factor (TNF). The studies presented here were undertaken to characterize mechanisms for the IL-12-induced toxicities and to examine expression and function of TNF in this context. Several physiological changes were induced in IL-12-treated uninfected and dramatically elevated in IL-12-treated virus-infected mice. IL-12 induced (a) decreases in body weights, &amp;gt; 10% in uninfected and &amp;gt; 20% in LCMV-infected mice; (b) elevation of circulating glucocorticoid levels to &amp;gt; 10 micrograms\/dl in uninfected and &amp;gt; 20 micrograms\/dl in infected mice; and (c) decreases in thymic mass, &amp;gt; 30% in uninfected and up to 95% in infected mice. These changes are known to be associated with circulating TNF. Northern blot and in situ hybridization analyses demonstrated that IL-12 induced TNF-alpha expression and that LCMV infection synergized with IL-12 for induction of this factor. Antibodies neutralizing TNF reversed all of the IL-12-induced toxicities in LCMV-infected mice including the immunotoxicities against CD8+ T cells and anti-viral defenses. The TNF-mediated immunotoxicities appeared to result from an induced cellular sensitivity to the factor, as splenic leukocytes and CD8+ T cell subsets isolated from LCMV-infected mice were more sensitive to TNF-mediated cytotoxicity in culture than were equivalent populations prepared from uninfected mice. Experiments with the glucocorticoid type II receptor antagonist, RU486, demonstrated that endogenous glucocorticoids were secondary intermediaries in IL-12-induced thymic atrophy. Studies in IL-2-deficient mice showed that the synergism was dependent upon endogenous IL-2. The results delineate a unique mechanism of TNF-mediated toxicity. In addition, they have significant implications concerning potential detrimental consequences of in vivo TNF induction and of IL-12 administration for protective anti-viral responses.<\/jats:p>","DOI":"10.1084\/jem.181.3.901","type":"journal-article","created":{"date-parts":[[2004,6,24]],"date-time":"2004-06-24T07:56:10Z","timestamp":1088063770000},"page":"901-914","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":154,"title":["Mechanism of interleukin 12-mediated toxicities during experimental viral infections: role of tumor necrosis factor and glucocorticoids."],"prefix":"10.1084","volume":"181","author":[{"given":"J S","family":"Orange","sequence":"first","affiliation":[{"name":"Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"T P","family":"Salazar-Mather","sequence":"additional","affiliation":[{"name":"Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S M","family":"Opal","sequence":"additional","affiliation":[{"name":"Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R L","family":"Spencer","sequence":"additional","affiliation":[{"name":"Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A H","family":"Miller","sequence":"additional","affiliation":[{"name":"Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"B S","family":"McEwen","sequence":"additional","affiliation":[{"name":"Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C A","family":"Biron","sequence":"additional","affiliation":[{"name":"Division of Biology and Medicine, Brown University, Providence, Rhode Island 02912."}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"291","container-title":["The Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/181\/3\/901\/1677094\/901.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/181\/3\/901\/1677094\/901.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T06:46:22Z","timestamp":1690267582000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/181\/3\/901\/50870\/Mechanism-of-interleukin-12-mediated-toxicities"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1995,3,1]]},"references-count":0,"journal-issue":{"issue":"3","published-print":{"date-parts":[[1995,3,1]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.181.3.901","relation":{},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[1995,3,1]]}}}