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

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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.