Clarification of Negative Feedback Mechanism in Cytokine Signaling by Using SSI-1 KO Mouse

细胞因子通过细胞的分化、增殖、凋亡等调控生物体内稳态发挥重要作用，这些作用主要通过JAK-STAT信号通路实现。SSI-1 （SOCS-1）是JAK-STAT信号的负反馈调控因子之一。SSI-1型KO小鼠出生时健康正常，出生后2周内死亡，胸腺、脾脏等淋巴器官淋巴细胞凋亡加速。我们检测了ssi -1对TNF-a信号的作用，因为细胞凋亡通常是由TNF-a或Fas引起的。缺乏SSI-1基因的小鼠胚胎成纤维细胞（mef）对tnf -a诱导的凋亡敏感。相反，被迫表达SSI-1 （SSI-1/L929）的L929细胞（小鼠成纤维细胞系）对tnf -a诱导的凋亡表现出抗性。此外，缺乏SSI-1基因的mef显示p38 MAP激酶的激活减少，SSI-1/L929细胞显示维持该激酶的激活。然而，其他SSI-1家族，如SSI-3和SSI-5，没有表现出这些影响。因此，这些发现表明SSI-1通过调节p38 MAP激酶抑制tnf -a诱导的细胞凋亡。

Cytokines play important roles in controlling homeostasis of organisms through cell differentiation, proliferation, and apoptosis, and these effects are mainly brought about by JAK-STAT signal pathway. SSI-1 (SOCS-1) is known as one of negative feedback regulators of JAK-STAT signaling. SSI-1 KO mice are healthy and normal at birth, but die within 2 weeks after birth with accelerated apoptosis of lymphocyte in lymphoid organs such as thymus and spleen. We examined function of SSI-1on TNF-a signaling because apoptosis generally is brought by TNF-a or Fas. Murine embryonic fiboblasts (MEFs) lacking the SSI-1 gene become sensitive to TNF-a-induced apoptosis. In contrast, L929 cells (murine fibroblast cell line) forced to express SSI-1 (SSI-1/L929) showed resistance to TNF-a-induced apoptosis. Also, MEFs lacking SSI-1 gene showed to decrease in an activation of p38 MAP kinase and SSI-1/L929 cells showed to sustain an activation of this kinase. Other families of SSI-1, however, such as SSI-3 and SSI-5, did not show these effects. Thus, these findings suggest that SSI-1 suppress TNF-a-induced apoptosis through regulation of p38 MAP kinase.