Abstract
Cellular FLICE-inhibitory protein (c-FLIP) inhibits death receptor-mediated apoptosis by specific interaction with FADD and procaspase-8, and may thus interfere with activation events mediated by FADD and caspase-8. Recent studies, however, suggest that c-FLIP also transmits activation signals. The role of c-FLIP on T-cell activation was examined here using several transgenic mice with variable c-FLIP expression. In all c-FLIP-transgenic mice, Fas-mediated apoptosis and in vitro activation-induced T-cell death were suppressed, and T-cell proliferation and IL-2 production were inhibited. c-FLIP transgene also promoted in vivo thymocyte death. Higher c-FLIP transgene expression was correlated with a more profound suppression of T-cell activation and a prominent disturbance in mature thymocyte development. There was no evidence of increased activation and proliferation in all c-FLIP-transgenic T cells examined. Instead, suppression of T-cell activation in c-FLIP-transgenic T cells could be a combinatory effect of FADD/caspase-8-dependent signals and c-FLIP-specific activities.
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Abbreviations
- AICD:
-
activation-induced cell death
- DED:
-
death effector domain
- DR:
-
death receptor
- ERK:
-
extracellular signal-regulated kinase
- FLIP:
-
FLICE-like inhibitory protein
- MAPK:
-
mitogen-activated protein kinase
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Acknowledgements
We thank Dr. Roger Perlmutter for p1017 vector, Dr. Dimitris Kioussis for the CD2 cassettes, Dr. Leo Wang for transgenic mice construction, and Dr. Ken Deen for editing the manuscript. This work was supported by a grant from Academia Sinica, Grant 90-2320-B001-059 from National Science Council, and Grant NHRI-Ex92-9217BI from National Health Research Institute, Taiwan, ROC.
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Tai, TS., Fang, LW. & Lai, MZ. c-FLICE inhibitory protein expression inhibits T-cell activation. Cell Death Differ 11, 69–79 (2004). https://doi.org/10.1038/sj.cdd.4401316
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DOI: https://doi.org/10.1038/sj.cdd.4401316
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