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

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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 livers 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 liver 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.
Funding Information
  • Ministry of Education, Culture, Sports, Science, and Technology of Japan
  • Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation (NIBIO)
  • Mochida Memorial Foundation
  • Naito Foundation
  • Yamanouchi Foundation of Research on Metabolic Disorders
  • Takeda Science Foundation
  • Kato Memorial Foundation
  • Uehara Memorial Foundation
  • Suzuken Memorial Foundation
  • Japan Intractable Disease Research Foundation
  • Ichiro Kanehara Memorial Foundation
  • NOVARTIS Foundation (Japan) for Promotion of Science
  • Mitsubishi Pharma Research Foundation
  • Clinical Research Foundation (2007)
  • Yakulto Bioscience Research Foundation