Suppressor of cytokine signaling 1 protects mice against concanavalin A-induced hepatitis by inhibiting apoptosis

Takehiro Torisu, Mako Nakaya, Satoko Watanabe, Masayuki Hashimoto, Hideyuki Yoshida, Takatoshi Chinen, Ryoko Yoshida, Fuyuki Okamoto, Toshikatsu Hanada, Kumiko Torisu, Giichi Takaesu, Takashi Kobayashi, Hideo Yasukawa, Akihiko Yoshimura

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Abstract

Acute liver failure is associated with significant mortality. However, the underlying pathophysiological mechanism is not yet fully understood. Suppressor of cytokine signaling-1 (SOCS1), which is a negative-feedback molecule for cytokine signaling, has been shown to be rapidly induced during liver injury. Here, using liver-specific SOCS1-conditional-knockout mice, we demonstrated that SOCS1 deletion in hepatocytes enhanced concanavalin A (ConA)-induced hepatitis, which has been shown to be dependent on activated T and natural killer T (NKT) cells. Although serum cytokine level and NKT cell activation were similar in wild-type (WT) and SOCS1-deficient mice after ConA treatment, proapoptotic signals, including signal transducers and activators of transcription 1 (STAT1) and Jun-terminal kinase (JNK) activation, were enhanced in SOCS1-deficient fivers compared with those in WT livers. SOCS1-deficient hepatocytes had higher expression of Fas antigen and were more sensitive to anti-Fas antibody-induced apoptosis than were WT hepatocytes. Furthermore, SOCS1-deficient hepatocytes were more sensitive to tumor necrosis factor (TNF)-α-induced JNK activation and apoptosis. These data indicate that SOCS1 is important to the prevention of hepatocyte apoptosis induced by Fas and TNF-α. In contrast, SOCS1 overexpression in the liver by adenoviral gene transfer prevented ConA-induced fiver injury. Conclusion: These findings indicate that SOCS1 plays important negative roles in fulminant hepatitis and that forced expression of SOCS1 is therapeutic in preventing hepatitis.

Original languageEnglish
Pages (from-to)1644-1654
Number of pages11
JournalHepatology
Volume47
Issue number5
DOIs
Publication statusPublished - 2008 May 1
Externally publishedYes

ASJC Scopus subject areas

  • Hepatology

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    Torisu, T., Nakaya, M., Watanabe, S., Hashimoto, M., Yoshida, H., Chinen, T., Yoshida, R., Okamoto, F., Hanada, T., Torisu, K., Takaesu, G., Kobayashi, T., Yasukawa, H., & Yoshimura, A. (2008). Suppressor of cytokine signaling 1 protects mice against concanavalin A-induced hepatitis by inhibiting apoptosis. Hepatology, 47(5), 1644-1654. https://doi.org/10.1002/hep.22214