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Dexamethasone protects primary cultured hepatocytes from death receptor-mediated apoptosis by upregulation of cFLIP.

Abstract

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.

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  • Authors+Show Affiliations

    ,

    Vascular System Research Center, College of Medicine, Kangwon National University, Chunchon, Kangwon-Do, Korea.

    , , , , , , , , , ,

    Source

    Cell death and differentiation 13:3 2006 Mar pg 512-23

    MeSH

    Animals
    Apoptosis
    CASP8 and FADD-Like Apoptosis Regulating Protein
    Caspase 3
    Caspase 8
    Caspase 9
    Caspase Inhibitors
    Caspases
    Cells, Cultured
    Cytochromes c
    Dactinomycin
    Death Domain Receptor Signaling Adaptor Proteins
    Dexamethasone
    Galactosamine
    Hepatocytes
    Intracellular Signaling Peptides and Proteins
    Mice
    Nucleic Acid Synthesis Inhibitors
    RNA Interference
    Rats
    Rats, Sprague-Dawley
    Receptors, Tumor Necrosis Factor
    Transcriptional Activation
    Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
    Tumor Necrosis Factor-alpha
    Up-Regulation
    fas Receptor

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    16167066

    Citation

    Oh, H-Y, et al. "Dexamethasone Protects Primary Cultured Hepatocytes From Death Receptor-mediated Apoptosis By Upregulation of CFLIP." Cell Death and Differentiation, vol. 13, no. 3, 2006, pp. 512-23.
    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. 2006;13(3):512-23.
    Oh, H. Y., Namkoong, S., Lee, S. J., Por, E., Kim, C. K., Billiar, T. R., ... Kim, Y. M. (2006). Dexamethasone protects primary cultured hepatocytes from death receptor-mediated apoptosis by upregulation of cFLIP. Cell Death and Differentiation, 13(3), pp. 512-23.
    Oh HY, et al. Dexamethasone Protects Primary Cultured Hepatocytes From Death Receptor-mediated Apoptosis By Upregulation of CFLIP. Cell Death Differ. 2006;13(3):512-23. PubMed PMID: 16167066.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Dexamethasone protects primary cultured hepatocytes from death receptor-mediated apoptosis by upregulation of cFLIP. AU - Oh,H-Y, AU - Namkoong,S, AU - Lee,S-J, AU - Por,E, AU - Kim,C-K, AU - Billiar,T R, AU - Han,J-A, AU - Ha,K-S, AU - Chung,H-T, AU - Kwon,Y-G, AU - Lee,H, AU - Kim,Y-M, PY - 2005/9/17/pubmed PY - 2006/4/21/medline PY - 2005/9/17/entrez SP - 512 EP - 23 JF - Cell death and differentiation JO - Cell Death Differ. VL - 13 IS - 3 N2 - 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. SN - 1350-9047 UR - https://www.unboundmedicine.com/medline/citation/16167066/Dexamethasone_protects_primary_cultured_hepatocytes_from_death_receptor_mediated_apoptosis_by_upregulation_of_cFLIP_ L2 - http://dx.doi.org/10.1038/sj.cdd.4401771 DB - PRIME DP - Unbound Medicine ER -