Suppressor of cytokine signaling 1 protects mice against concanavalin A-induced hepatitis by inhibiting apoptosis
| Autor: | Giichi Takaesu, Takashi Kobayashi, Satoko Watanabe, Ryoko Yoshida, Takehiro Torisu, Fuyuki Okamoto, Akihiko Yoshimura, Masayuki Hashimoto, Hideyuki Yoshida, Mako Nakaya, Hideo Yasukawa, Kumiko Torisu, Toshikatsu Hanada, Takatoshi Chinen |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
medicine.medical_treatment
Apoptosis Enzyme-Linked Immunosorbent Assay Suppressor of Cytokine Signaling Proteins Hepatitis Animal Biology Mice Suppressor of Cytokine Signaling 1 Protein Concanavalin A medicine Animals Lymphocytes STAT1 Mice Knockout Hepatitis Liver injury Hepatology Reverse Transcriptase Polymerase Chain Reaction Suppressor of cytokine signaling 1 Flow Cytometry medicine.disease Mice Inbred C57BL Disease Models Animal Cytokine Liver Acute Disease Immunology Cancer research biology.protein RNA Tumor necrosis factor alpha Liver Failure |
| Zdroj: | Hepatology. 47:1644-1654 |
| ISSN: | 0270-9139 |
| DOI: | 10.1002/hep.22214 |
| Popis: | 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. (HEPATOLOGY 2008.) |
| Databáze: | OpenAIRE |
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