{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T07:25:01Z","timestamp":1769153101465,"version":"3.49.0"},"reference-count":49,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2007,3,1]],"date-time":"2007-03-01T00:00:00Z","timestamp":1172707200000},"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":[[2007,3,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Cytokines have been implicated in the progression of acetaminophen (APAP)-induced acute liver injury. Suppressors of cytokine signaling (SOCS) proteins are negative regulators of cytokine signaling by inhibiting the JAK-STAT pathway, but their role in APAP hepatotoxicity is unknown. In this present study, we attempted to explore the role of SOCS3 in T cells in APAP-induced liver injury. Mice with a cell-specific overexpression of SOCS3 in T cells (SOCS3Tg, in which Tg is transgenic) exhibited exaggerated hepatic injury after APAP challenge, as evidenced by increased serum alanine aminotransferase levels, augmented hepatic necrosis, and decreased survival relative to the wild-type mice. Adaptive transfer of SOCS3Tg-CD4+ T cells into T and B cell-deficient RAG-2\u2212\/\u2212 mice resulted in an exacerbated liver injury relative to the control. In SOCS3Tg mice, hepatocyte apoptosis was enhanced with decreased expression of antiapoptotic protein bcl-2, whereas hepatocyte proliferation was reduced with altered cell cycle-regulatory proteins. Levels of IFN-\u03b3 and TNF-\u03b1 in the circulation were augmented in SOCS3Tg mice relative to the control. Studies using neutralizing Abs indicated that elevated IFN-\u03b3 and TNF-\u03b1 were responsible for the exacerbated hepatotoxicity in SOCS3Tg mice. Activation of STAT1 that is harmful in liver injury was augmented in SOCS3Tg hepatocytes. Alternatively, hepatoprotective STAT3 activation was decreased in SOCS3Tg hepatocytes, an event that was associated with augmented SOCS3 expression in the hepatocytes. Altogether, these results suggest that forced expression of SOCS3 in T cells is deleterious in APAP hepatotoxicity by increasing STAT1 activation while decreasing STAT3 activation in hepatocytes, possibly through elevated IFN-\u03b3 and TNF-\u03b1.<\/jats:p>","DOI":"10.4049\/jimmunol.178.6.3777","type":"journal-article","created":{"date-parts":[[2014,4,18]],"date-time":"2014-04-18T23:26:46Z","timestamp":1397863606000},"page":"3777-3785","source":"Crossref","is-referenced-by-count":42,"title":["Overexpression of Suppressor of Cytokine Signaling-3 in T Cells Exacerbates Acetaminophen-Induced Hepatotoxicity"],"prefix":"10.1093","volume":"178","author":[{"given":"Kosuke","family":"Numata","sequence":"first","affiliation":[{"name":"Departments of Pathology and Experimental Medicine, Kumamoto University , Kumamoto ,","place":["Japan"]},{"name":"Orthopaedic and Neuro-Musculoskeletal Surgery, Graduate School of Medical Sciences, Kumamoto University , Kumamoto ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masato","family":"Kubo","sequence":"additional","affiliation":[{"name":"Laboratory for Signal Network, RIKEN Research Center for Allergy and Immunology , Yokohama ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroyuki","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Departments of Pathology and Experimental Medicine, Kumamoto University , Kumamoto ,","place":["Japan"]},{"name":"Orthopaedic and Neuro-Musculoskeletal Surgery, Graduate School of Medical Sciences, Kumamoto University , Kumamoto ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katsumasa","family":"Takagi","sequence":"additional","affiliation":[{"name":"Orthopaedic and Neuro-Musculoskeletal Surgery, Graduate School of Medical Sciences, Kumamoto University , Kumamoto ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroshi","family":"Mizuta","sequence":"additional","affiliation":[{"name":"Orthopaedic and Neuro-Musculoskeletal Surgery, Graduate School of Medical Sciences, Kumamoto University , Kumamoto ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seiji","family":"Okada","sequence":"additional","affiliation":[{"name":"Division of Hematopoiesis, Center for AIDS Research, Kumamoto University , Kumamoto ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steven L","family":"Kunkel","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Michigan Medical School , Ann Arbor, MI 48109"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takaaki","family":"Ito","sequence":"additional","affiliation":[{"name":"Departments of Pathology and Experimental Medicine, Kumamoto University , Kumamoto ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akihiro","family":"Matsukawa","sequence":"additional","affiliation":[{"name":"Departments of Pathology and Experimental Medicine, Kumamoto University , Kumamoto ,","place":["Japan"]},{"name":"Department of Pathology and Experimental Medicine, Graduate School of Medical, Dentistry and Pharmaceutical Sciences, Okayama University , Okayama ,","place":["Japan"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2007,3,15]]},"reference":[{"key":"2025032802312312500_R1","first-page":"1311","volume-title":"N. 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