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 inhibitor-1 [SSI-1; also known as suppressor of cytokine signaling-1 (SOCS-1)] was identified as a negative feedback regulator of Janus kinase-STAT signaling. We previously generated mice lacking the SSI-1 gene (SSI-1 -/-) and showed that thymocytes and splenocytes in SSI-1 -/- mice underwent accelerated apoptosis. In this paper, we show that murine embryonic fibroblasts lacking the SSI-1 gene are more sensitive than their littermate controls to tumor necrosis factor-alpha (TNF-alpha)-induced cell death. In addition, L929 cells forced to express SSI-1 (L929/SSI-1), but not SSI-3 or SOCS-5, are resistant to TNF-alpha-induced cell death. Furthermore L929/SSI-1 cells treated with TNF-alpha sustain the activation of p38 mitogen-activated protein (MAP) kinase. In contrast, SSI-1 -/- murine embryonic fibroblasts treated with TNF-alpha show hardly any activation of p38 MAP kinase. These findings suggest that SSI-1 suppresses TNF-alpha-induced cell death, which is mediated by p38 MAP kinase signaling.
Morita
Y
Y
Department of Medicine III, Osaka University Medical School, 2-2, Yamada-oka, Suita-city, Osaka 565-0871, Japan.
Naka
T
T
Kawazoe
Y
Y
Fujimoto
M
M
Narazaki
M
M
Nakagawa
R
R
Fukuyama
H
H
Nagata
S
S
Kishimoto
T
T
D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D007093:Imidazoles / Q000494:pharmacology; D007371:Interferon-gamma / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D007700:Kinetics; D007739:L Cells; D051379:Mice; D018345:Mice, Knockout; D011725:Pyridines / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology* / Q000502:physiology*; D000077191:Wortmannin
D000730:Androstadienes; D002352:Carrier Proteins; D061945:Caspase Inhibitors; D016207:Cytokines; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007375:Interleukin-1; D011725:Pyridines; D011994:Recombinant Proteins; D012097:Repressor Proteins; D050794:STAT1 Transcription Factor; C491590:Socs1 protein, mouse; C494080:Stat1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; C093642:SB 203580; D000077191:Wortmannin