Dexamethasone protects primary cultured hepatocytes from death receptor-mediated apoptosis by upregulation of cFLIP.
Dexamethasone (DEX) pretreatment protected hepatocytes from TNF-alpha 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.
Vascular System Research Center, College of Medicine, Kangwon National University, Chunchon, Kangwon-Do, Korea., , , , , , , , , ,
CASP8 and FADD-Like Apoptosis Regulating Protein
Death Domain Receptor Signaling Adaptor Proteins
Intracellular Signaling Peptides and Proteins
Nucleic Acid Synthesis Inhibitors
Receptors, Tumor Necrosis Factor
Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
Tumor Necrosis Factor-alpha
Pub Type(s)Journal Article
Research Support, Non-U.S. Gov't