The farnesyltransferase inhibitor tipifarnib protects against autoimmune hepatitis induced by Concanavalin A
The farnesyltransferase inhibitor tipifarnib protects against autoimmune hepatitis induced by Concanavalin A
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DOI：
10.1016/j.intimp.2020.106462
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发表时间：
2020-06-01
影响因子：
5.6
通讯作者：
Yamaura, Ken
中科院分区：
文献类型：
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作者：
Guo, Jie;Shirozu, Kazuhiro;Yamaura, Ken
除了在致命阶段进行肝移植外，还没有建立有效的治疗自身免疫性肝炎（AIH）的方法。法尼基转移酶抑制剂（FTIs）在AIH治疗中的作用和机制尚不清楚。因此，我们研究了FTI，tipifarnib，在伴刀豆球蛋白A（Con A）诱导的肝炎模型的具体作用。通过组织学、生化和免疫学分析，研究了替吡法尼（10 mg/kg，腹腔注射）在Con A（20 mg/kg，静脉注射）攻击小鼠中的作用。将替吡法尼处理的小鼠与磷酸盐缓冲盐水（PBS）处理的小鼠进行比较。Con A引起肝损伤，其特征在于血浆丙氨酸氨基转移酶（ALT）水平升高和显著的组织学变化。在2或8 h观察到血清ALT、白细胞介素-6或干扰素-γ（IFN-γ）水平升高;替吡法尼组Con A给药后2 h肿瘤坏死因子-α水平显著降低。Tipifarnib还抑制了肝脏和脾脏中Con A诱导的CD 4（+）细胞（但不是CD 8（+）T细胞）的活化，并逆转了肝脏中Con A诱导的自然杀伤T（NKT）细胞的减少。在Con A给药后2小时，Tipifarnib显著抑制肝脏中CD 4（+）T细胞（但不抑制CD 8（+）T和NKT细胞）的IFN-γ产生和STAT 1磷酸化。Tipifarnib在体外显著抑制ConA注射后48 h脾CD 4（+）T细胞产生IFN-γ。替吡法尼还抑制Con A诱导的法尼基化蛋白的表达。总之，由于下调STAT 1磷酸化，tipifarnib抑制了Con A诱导的CD 4（+）T细胞活化产生的IFN-γ，表明Tipifarnib可以预防AIH。
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-gamma (IFN-gamma) levels were observed at 2 or 8 h; tumor necrosis factor-alpha 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-gamma 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-gamma 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-gamma derived from Con A-induced CD4(+) T cell activation due to downregulated STAT1 phosphorylation, suggesting that Tipifarnib can protect against AIH.