The farnesyltransferase inhibitor tipifarnib protects against autoimmune hepatitis induced by Concanavalin A

• Published in: International immunopharmacology 2020-06, Vol.83, p.106462-106462, Article 106462
• Main Authors: Guo, Jie, Shirozu, Kazuhiro, Akahoshi, Tomohiko, Mizuta, Yukie, Murata, Masaharu, Yamaura, Ken
• Format: Article
• Language: English
• Subjects: Alanine; Alanine transaminase; Animals; Antineoplastic Agents - therapeutic use; Autoimmune hepatitis; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD8 antigen; Cell activation; Cells, Cultured; Concanavalin A; Concanavalin A - metabolism; Disease Models, Animal; Farnesyltransferase; Farnesyltransferase inhibitors; Hepatitis; Hepatitis, Autoimmune - drug therapy; Hepatitis, Autoimmune - immunology; Hepatocytes; Humans; Immunology; Injection; Interferon; Interferon-gamma - metabolism; Interleukin 6; Intravenous administration; Liver; Liver - immunology; Liver transplantation; Lymphocyte Activation; Lymphocytes; Lymphocytes T; Male; Mice; Mice, Inbred C57BL; Natural killer cells; Phosphorylation; Quinolones - therapeutic use; Spleen; STAT; Stat1 protein; Tipifarnib; Transplantation; Tumor necrosis factor-α; γ-Interferon
• ISSN: 1567-5769; 1878-1705
• DOI: 10.1016/j.intimp.2020.106462

•Con A induced liver injury with increased plasma ALT and histological changes.•Tipifarnib blocked Con A-dependent increases in serum ALT, IL-6, TNF-α, and IFN-γ.•Tipifarnib suppressed Con A-induced activation of hepatic and splenic CD4+ cells.•Tipifarnib lowered IFN-γ levels and STAT1 phosphorylation in hepatic CD4+ T cells. No effective treatment has been established for autoimmune hepatitis (AIH), except for liver transplantation in the fatal stage. Little is known about the roles and mechanisms of farnesyltransferase inhibitors (FTIs) in treating AIH. Thus, we investigated the specific role of the FTI, tipifarnib, in a Concanavalin A (Con A)-induced model of hepatitis. The effects of tipifarnib (10 mg/kg, intraperitoneal injection) were studied in Con A (20 mg/kg, intravenous injection)-challenged mice by histological, biochemical, and immunological analyses. Tipifarnib-treated mice were compared to phosphate-buffered saline (PBS)-treated mice. Con A caused liver injury characterized by increased plasma alanine aminotransferase (ALT) levels and marked histological changes. The increased serum ALT, interleukin-6, or interferon-γ (IFN-γ) levels were observed at 2 or 8 h; tumor necrosis factor-α levels at 2 h post-Con A administration decreased significantly in the tipifarnib group. Tipifarnib also suppressed Con A-induced activation of CD4+ cells (but not CD8+ T cells) in the liver and spleen, and also reversed the Con A-induced decrease of natural killer T (NKT) cells in the liver. Tipifarnib significantly inhibited IFN-γ production and STAT1 phosphorylation from CD4+ T cells (but not CD8+ T and NKT cells) in the liver at 2 h post-Con A administration. Tipifarnib significantly inhibited IFN-γ production by splenic CD4+ T cells at 48 h post-Con A injection in vitro. Tipifarnib also inhibited the expression of farnesylated proteins induced by Con A administration. In conclusion, tipifarnib inhibited IFN-γ derived from Con A-induced CD4+ T cell activation due to downregulated STAT1 phosphorylation, suggesting that Tipifarnib can protect against AIH.