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* Departments of Pathology and Experimental Medicine and
Orthopaedic and Neuro-Musculoskeletal Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan;
Laboratory for Signal Network, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan;
Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto, Japan;
¶ Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109; and
|| Department of Pathology and Experimental Medicine, Graduate School of Medical, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
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-
and TNF-
in the circulation were augmented in SOCS3Tg mice relative to the control. Studies using neutralizing Abs indicated that elevated IFN- and TNF- 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- and TNF-.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported in part by grants from the Ministry of Education, Science, Sports and Culture and the Ministry of Health and Welfare, Japan.
2 Address correspondence and reprint requests to Dr. Akihiro Matsukawa, Department of Pathology and Experimental Medicine, Graduate School of Medical, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1, Shikata, Okayama 700-8558, Japan. E-mail address: amatsu{at}md.okayama-u.ac.jp
3 Abbreviations used in this paper: APAP, acetaminophen; ALT, alanine aminotransferase; NAPQI, N-acetyl-p-benzoquinoneimine; SOCS, suppressors of cytokine signaling; Tg, transgenic; WT, wild type; FasL, Fas ligand.
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