Signals transducers and activators of transcription (STAT)-induced STAT inhibitor-1 (SSI-1)/suppressor of cytokine signaling-1 (SOCS-1) suppresses tumor necrosis factor alpha-induced cell death in fibroblasts

Signal transducers and activators of transcription (STAT)-induced STAT inhi bitor-1 [SSI-1; also known as suppressor of cytokine signaling-1 (SOCS-1)] was identified as a negative feedback regulator of Janus kinase-STAT signal ing. We previously generated mice lacking the SSI-1 gene (SSI-1 -/-) and sh owed that thymocytes and splenocytes in SSI-1 -/- mice underwent accelerate d apoptosis. In this paper, we show that murine embryonic fibroblasts lacki ng the SSI-1 gene are more sensitive than their littermate controls to tumo r necrosis factor-alpha (TNF-alpha)-induced cell death. In addition, L929 c ells forced to express SSI-l (L929/SSI-1), but not SSI-3 or SOCS-5, are res istant to TNF-alpha-induced cell death. Furthermore L929/SSI-1 cells treate d with TNF-alpha sustain the activation of p38 mitogen-activated protein (M AP) kinase. In contrast, SSI-1 -/- murine embryonic fibroblasts treated wit h TNF-alpha show hardly any activation of p38 MAP kinase. These findings su ggest that SSI-1 suppresses TNF-alpha-induced cell death, which is mediated by p38 MAP kinase signaling.