Overexpression of suppressor of cytokine signaling-3 in T cells exacerbates acetaminophen-induced hepatotoxicity

Kosuke Numata, Masato Kubo, Hiroyuki Watanabe, Katsumasa Takagi, Hiroshi Mizuta, Seiji Okada, Steven L. Kunkel, Takaaki Ito, Akihiro Matsukawa

Research output: Contribution to journalArticle

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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-γ and TNF-α in the circulation were augmented in SOCS3Tg mice relative to the control. Studies using neutralizing Abs indicated that elevated IFN-γ and TNF-α 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 STATS 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-γ and TNF-α.

Original languageEnglish
Pages (from-to)3777-3785
Number of pages9
JournalJournal of Immunology
Volume178
Issue number6
Publication statusPublished - Mar 15 2007

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Acetaminophen
Hepatocytes
Cytokines
T-Lymphocytes
Liver
Wounds and Injuries
Suppressor of Cytokine Signaling Proteins
Cell Cycle Proteins
Alanine Transaminase
B-Lymphocytes
Necrosis
Apoptosis
Serum
Proteins

ASJC Scopus subject areas

  • Immunology

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Overexpression of suppressor of cytokine signaling-3 in T cells exacerbates acetaminophen-induced hepatotoxicity. / Numata, Kosuke; Kubo, Masato; Watanabe, Hiroyuki; Takagi, Katsumasa; Mizuta, Hiroshi; Okada, Seiji; Kunkel, Steven L.; Ito, Takaaki; Matsukawa, Akihiro.

In: Journal of Immunology, Vol. 178, No. 6, 15.03.2007, p. 3777-3785.

Research output: Contribution to journalArticle

Numata, K, Kubo, M, Watanabe, H, Takagi, K, Mizuta, H, Okada, S, Kunkel, SL, Ito, T & Matsukawa, A 2007, 'Overexpression of suppressor of cytokine signaling-3 in T cells exacerbates acetaminophen-induced hepatotoxicity', Journal of Immunology, vol. 178, no. 6, pp. 3777-3785.
Numata K, Kubo M, Watanabe H, Takagi K, Mizuta H, Okada S et al. Overexpression of suppressor of cytokine signaling-3 in T cells exacerbates acetaminophen-induced hepatotoxicity. Journal of Immunology. 2007 Mar 15;178(6):3777-3785.
Numata, Kosuke ; Kubo, Masato ; Watanabe, Hiroyuki ; Takagi, Katsumasa ; Mizuta, Hiroshi ; Okada, Seiji ; Kunkel, Steven L. ; Ito, Takaaki ; Matsukawa, Akihiro. / Overexpression of suppressor of cytokine signaling-3 in T cells exacerbates acetaminophen-induced hepatotoxicity. In: Journal of Immunology. 2007 ; Vol. 178, No. 6. pp. 3777-3785.
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