Interferon-alpha induces transient upregulation of c-FLIP through NF-kappaB activation

Exp Cell Res. 2008 Jan 15;314(2):246-54. doi: 10.1016/j.yexcr.2007.10.001. Epub 2007 Oct 5.


Interferon-alpha (IFN-alpha) induces apoptosis in some cell types and promotes cell survival in other cell types, but the molecular mechanisms underlying distinct IFN-alpha-induced cell behaviours remain poorly understood. In the present study, we show that IFN-alpha induced the cellular FLICE (FADD-like interleukin-1 beta-converting enzyme) inhibitory protein (c-FLIP), which serves as a promoter of cell survival in human B lymphoma cells. IFN-alpha induction of transient upregulation of c-FLIP was partially abrogated by the NF-kappaB inhibitor BAY11-7082 (BAY). Pretreatment with BAY sensitized both Daudi and U266 cells to the IFN-alpha-induced loss of mitochondrial membrane potential (DeltaPsi(m)). IFN-alpha phosphorylated the PKC isoform PKCalpha at a threonine residue, and the PKCalpha/betaI inhibitor Go6976 abrogated upregulation of IFN-alpha-induced NF-kappaB activity, leading to sensitization of cells to IFN-alpha-induced apoptosis. To analyze the role of PKCalpha in the IFN-alpha-induced signaling, Daudi cells overexpressing a constitutively active mutant of PKCalpha (caPKCalpha) were used. The caPKCalpha-expressing Daudi cells were partially resistant to the IFN-alpha-induced loss of DeltaPsi(m), concomitant with elevated levels of c-FLIP protein. Together, these results demonstrate that IFN-alpha causes a transient upregulation of c-FLIP expression, at least through PKCalpha-mediated activation of NF-kappaB. The balance between IFN-alpha-induced pro-apoptotic and survival signals determines the cell fate. Thus, therapeutic intervention in this balance may be effective for treatment of patients with IFN-alpha-refractory tumours.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis
  • CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
  • CASP8 and FADD-Like Apoptosis Regulating Protein / metabolism*
  • Cell Line, Tumor
  • Humans
  • Immunologic Factors / metabolism
  • Immunologic Factors / pharmacology*
  • Interferon-alpha / metabolism
  • Interferon-alpha / pharmacology*
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • Nitriles / pharmacology
  • Protein Kinase C-alpha / metabolism
  • RNA, Messenger / metabolism
  • Signal Transduction
  • Sulfones / pharmacology
  • Time Factors
  • Up-Regulation*


  • 3-(4-methylphenylsulfonyl)-2-propenenitrile
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Immunologic Factors
  • Interferon-alpha
  • NF-kappa B
  • Nitriles
  • RNA, Messenger
  • Sulfones
  • Protein Kinase C-alpha