SOCS3 in T and NKT Cells Negatively Regulates Cytokine Production and Ameliorates ConA-Induced Hepatitis
SOCS3 in T and NKT Cells Negatively Regulates Cytokine Production and Ameliorates ConA-Induced Hepatitis
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DOI：
10.4049/jimmunol.0900547
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发表时间：
2009-12-01
影响因子：
4.4
通讯作者：
Yoshimura, Akihiko
中科院分区：
文献类型：
--
作者：
Nakaya, Mako;Hashimoto, Masayuki;Yoshimura, Akihiko
细胞因子信号传导抑制剂 3 (SOCS3) 是细胞因子信号传导的负反馈分子，与预防肝损伤有关。先前的研究表明，腺病毒或透膜重组蛋白在肝脏中过度表达SOCS3可以保护肝脏免受各种损伤。然而，尚不清楚 SOCS3 在哪种类型的细胞中抑制肝损伤。在这项研究中，我们使用 T 和 NKT 细胞特异性 SOCS3 转基因 (Lck-SOCS3 Tg) 小鼠证明，在 T 和 NKT 细胞中强制表达 SOCS3 可抑制 ConA 诱导的肝炎。 Lck-SOCS3 Tg 小鼠以及用 ConA 处理的脾细胞中 IFN-γ 和 IL-4 的产生减少。给予α-半乳糖神经酰胺的Lck-SOCS3 Tg小鼠中IFN-γ和IL-4水平也降低，表明NKT细胞中的SOCS3具有抑制功能。 SOCS3 在 NKT 细胞系中的持续表达也会导致各种细胞因子和转录因子的表达减少。相比之下，T 和 NKT 细胞特异性 SOCS3 条件性敲除 (Lck-SOCS3 cKO) 小鼠对 ConA 介导的肝炎高度敏感。分离的 SOCS3 缺陷型 NKT 细胞产生更高水平的 IFN-γ 和 IL-4。这些数据表明SOCS3在NKT细胞活化中发挥负调节作用，并且在NKT细胞中强制表达SOCS3可有效预防肝炎。免疫学杂志，2009，183：7047-7053。
Suppressor of cytokine signaling 3 (SOCS3), a negative-feedback molecule for cytokine signaling, has been implicated in protection against liver injury. Previous studies have shown that overexpression of SOCS3 in the liver by adenovirus or membrane permeable recombinant protein protected the liver from various injuries. However it remained uncertain in which type of cells SOCS3 suppresses liver injury. In this study, we demonstrated that forced expression of SOCS3 in T and NKT cells suppressed ConA-induced hepatitis using T and NKT cell-specific SOCS3 transgenic (Lck-SOCS3 Tg) mice. IFN-gamma and IL-4 production was reduced in Lck-SOCS3 Tg mice as well as splenocytes treated with ConA. IFN-gamma and IL-4 levels were also reduced in Lck-SOCS3 Tg mice administrated with alpha-galactosylceramide, suggesting that SOCS3 in NKT cells has suppressive function. Sustained expression of SOCS3 in an NKT cell line also resulted in reduced expression of various cytokines and transcription factors. In contrast, T and NKT cell-specific SOCS3 conditional knockout (Lck-SOCS3 cKO) mice were hypersensitive to ConA-mediated hepatitis. Isolated SOCS3-deficient NKT cells produced higher levels of IFN-gamma and IL-4. These data indicate that SOCS3 plays a negative regulatory role in NKT cell activation and that forced expression of SOCS3 in NKT cells is effective in preventing hepatitis. The Journal of Immunology, 2009, 183: 7047-7053.