Abstract
Dexamethasone (DEX) pretreatment protected hepatocytes from TNF-α plus actinomycin D (ActD)-induced apoptosis by suppressing caspase-8 activation and the mitochondria-dependent apoptosis pathway. DEX treatment upregulated cellular FLICE inhibitory protein (cFLIP) expression, but did not alter the protein levels of Bcl-2, Bcl-xL, Mcl-1, and cIAP as well as Akt activation. The increased cFLIP mRNA level by DEX was inhibited by ActD, indicating that DEX upregulates cFLIP expression at the transcriptional step. DEX also inhibited Jo2-mediated hepatocyte apoptosis by blocking the formation of the death-inducing signaling complex and caspase-8 activation. Specific downregulation of cFLIP expression using siRNA reversed the antiapoptotic effect of DEX by increasing caspase-8 activation. Moreover, DEX administration into mice increased cFLIP expression in the liver and prevented Jo2-induced hepatic injury by inhibiting caspase-8 and -3 activities. Our results indicate that DEX exerts a protective role in death receptor-induced in vitro and in vivo hepatocyte apoptosis by upregulating cFLIP expression.
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Abbreviations
- DEX:
-
dexamethasone
- TNF-α:
-
tumor necrosis factor-alpha
- ActD:
-
actinomycin
- GalN:
-
galactosamine
- cFLIP:
-
cellular FLICE inhibitory protein
- TNF-R:
-
TNF-α receptor
- FADD:
-
Fas-associated death domain-containing protein
- DISC:
-
death-inducing signaling complex
- IETDase:
-
caspase-8-like enzyme
- LEHDase:
-
caspase-9-like enzyme
- DEVDase:
-
caspase-3-like enzyme
- CAD:
-
caspase-activated DNase
- PARP:
-
poly(ADP-ribose) polymerase
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This work was supported by Vascular System Research Center grant from Korea Science and Engineering Foundation.
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H-Y Oh, S Namkoong: These authors contributed equally to this work.
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Oh, HY., Namkoong, S., Lee, SJ. et al. Dexamethasone protects primary cultured hepatocytes from death receptor-mediated apoptosis by upregulation of cFLIP. Cell Death Differ 13, 512–523 (2006). https://doi.org/10.1038/sj.cdd.4401771
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DOI: https://doi.org/10.1038/sj.cdd.4401771
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