title: Overexpression of suppressor of cytokine signaling-3 in T cells exacerbates acetaminophen-induced hepatotoxicity.
abstract: 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(-/-) 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-gamma and TNF-alpha in the circulation were augmented in SOCS3Tg mice relative to the control. Studies using neutralizing Abs indicated that elevated IFN-gamma and TNF-alpha 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-gamma and TNF-alpha.
authors.affiliation: Department of Pathology and Experimental Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Numata
authors.forename: Masato
authors.initials: M
authors.lastname: Kubo
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Watanabe
authors.forename: Katsumasa
authors.initials: K
authors.lastname: Takagi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mizuta
authors.forename: Seiji
authors.initials: S
authors.lastname: Okada
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kunkel
authors.forename: Takaaki
authors.initials: T
authors.lastname: Ito
authors.forename: Akihiro
authors.initials: A
authors.lastname: Matsukawa
mesh_terms: D000082:Acetaminophen / Q000633:toxicity*; D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D022781:Hepatocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006609:High Mobility Group Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000276:immunology / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D055748:SOXB1 Transcription Factors; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology
chemical_list: D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C499308:Rag2 protein, mouse; D055748:SOXB1 Transcription Factors; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C527786:Sox3 protein, mouse; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D014157:Transcription Factors; C052617:Bcl2 protein, mouse; D000082:Acetaminophen; D007371:Interferon-gamma