Inhibition of cellular FLICE-like inhibitory protein abolishes insensitivity to interferon-α and death receptor stimulation in resistant variants of the human ... View Full Text


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Article Info

DATE

2011-05-12

AUTHORS

Jeanette Blomberg, Andreas Höglund, David Eriksson, Kristina Ruuth, Maria Jacobsson, Erik Lundgren, Jonas A. Nilsson

ABSTRACT

Type I interferons constitute a family of pleiotropic cytokines that have a key role in both adaptive and innate immunity. The interferon signalling pathways mediate transcriptional regulation of hundreds of genes, which result in mRNA degradation, decreased protein synthesis, cell cycle inhibition and induction of apoptosis. To elucidate regulatory networks important for interferon induced cell death, we generated interferon resistant U937 cells by selection in progressively increasing concentrations of interferon-α (IFN-α). The results show that IFN-α activates the death receptor signalling pathway and that IFN resistance was associated with cross-resistance to several death receptor ligands in a manner similar to previously described Fas resistant U937 cell lines. Increased expression of the long splice variant of the cellular FLICE-like inhibitor protein (cFLIP-L) was associated with the resistance to death receptor and IFN-α stimulation. Accordingly, inhibition of cFLIP-L expression with cycloheximide or through cFLIP short harpin RNA interference restored sensitivity to Fas and/or IFN-α. Thus, we now show that selection for interferon resistance can generate cells with increased expression of cFLIP, which protects the cells from both IFN-α and death receptor mediated apoptosis. More... »

PAGES

783-794

References to SciGraph publications

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  • 2003-05-02. Involvement of interferon regulatory factor-1 in monocyte CD95 expression and CD95-mediated apoptosis in CELL DEATH & DIFFERENTIATION
  • 2007-12. Interferons at age 50: past, current and future impact on biomedicine in NATURE REVIEWS DRUG DISCOVERY
  • 2001-03. Apoptosis and cell growth inhibition as antitumor effector functions of interferons in MEDICAL ONCOLOGY
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  • 2007-04-23. Interferon regulatory factor-1-induced apoptosis mediated by a ligand-independent fas-associated death domain pathway in breast cancer cells in ONCOGENE
  • 2002-02-14. Mechanisms of Interferon-alpha induced apoptosis in malignant cells in ONCOGENE
  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1007/s10495-011-0606-0

    DOI

    http://dx.doi.org/10.1007/s10495-011-0606-0

    DIMENSIONS

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    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/21562857


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    38 schema:description Type I interferons constitute a family of pleiotropic cytokines that have a key role in both adaptive and innate immunity. The interferon signalling pathways mediate transcriptional regulation of hundreds of genes, which result in mRNA degradation, decreased protein synthesis, cell cycle inhibition and induction of apoptosis. To elucidate regulatory networks important for interferon induced cell death, we generated interferon resistant U937 cells by selection in progressively increasing concentrations of interferon-α (IFN-α). The results show that IFN-α activates the death receptor signalling pathway and that IFN resistance was associated with cross-resistance to several death receptor ligands in a manner similar to previously described Fas resistant U937 cell lines. Increased expression of the long splice variant of the cellular FLICE-like inhibitor protein (cFLIP-L) was associated with the resistance to death receptor and IFN-α stimulation. Accordingly, inhibition of cFLIP-L expression with cycloheximide or through cFLIP short harpin RNA interference restored sensitivity to Fas and/or IFN-α. Thus, we now show that selection for interferon resistance can generate cells with increased expression of cFLIP, which protects the cells from both IFN-α and death receptor mediated apoptosis.
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