International Immunology Advance Access originally published online on June 1, 2004
International Immunology 2004 16(7):991-999; doi:10.1093/intimm/dxh102
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International Immunology, Vol. 16, No. 7, pp. 991-999,
July 2004
© 2004 Japanese Society for Immunology
SOCS-1 suppresses TNF-
-induced apoptosis through the regulation of Jak activation
1 Department of Molecular Medicine, Osaka University Graduate School of Medicine, 2-2, Yamada-oka, Suita, Osaka, 565-0871, Japan 2 Department of Genetics, Osaka University Medical School, 2-2, Yamada-oka, Suita, Osaka, 565-0871, Japan 3 Laboratory of Immune Regulation, Graduate School of Frontier Biosciences, Osaka University, 1-3, Yamada-oka, Suita, Osaka, 565-0871, Japan
Correspondence to: T. Kishimoto; E-mail: a.kimura{at}imed3.med.osaka-u.ac.jp
Transmitting editor: T. Watanabe
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-
(TNF-)-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-. We also show that the activations of Jaks and caspases by TNF- are suppressed by SOCS-1. Furthermore, in Jak-deficient cell lines, DNA fragmentation and caspase-8 activation by TNF- are suppressed, indicating that Jaks participate in TNF--induced apoptosis signaling. Taken together, these results suggest that SOCS-1 inhibits TNF--induced apoptosis through regulation of Jaks.
Keywords: caspase, cell death, negative feedback regulator, TNFR-1, tyrosine kinase
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