Suppressor of cytokine signaling-1 (SOCS-1) was identified as one of the negative feedback regulators of Janus kinase (Jak)-signal-transducer-and-activator-of-transcription (STAT) signaling. So far, it has been reported that SOCS-1 inhibits the action of multiple cytokines at least in vitro. We previously showed that SOCS-1 suppresses tumor necrosis factor-α (TNF-α)-induced apoptosis in murine embryonic fibroblast, but the mechanism of suppression was not fully clarified. In this study, we show that Jaks bind to TNF receptor-1 (TNFR-1) and are activated by TNF-α. We also show that the activations of Jaks and caspases by TNF-α are suppressed by SOCS-1. Furthermore, in Jak-deficient cell lines, DNA fragmentation and caspase-8 activation by TNF-α are suppressed, indicating that Jaks participate in TNF-α-induced apoptosis signaling. Taken together, these results suggest that SOCS-1 inhibits TNF-α-induced apoptosis through regulation of Jaks.
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