Interferon-α induces transient upregulation of c-FLIP through NF-κB activation

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