Interferon-alpha induces transient upregulation of c-FLIP through NF-kappaB activation.
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.
Kanetaka
Yuki
Y
Department of Immunology and Intractable Immune System Disease Research Center, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan.
Hayashida
Miho
M
Hoshika
Akinori
A
Yanase
Noriko
N
Mizuguchi
Junichiro
J
D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D007155:Immunologic Factors / Q000378:metabolism / Q000494:pharmacology*; D016898:Interferon-alpha / Q000378:metabolism / Q000494:pharmacology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D051571:Protein Kinase C-alpha / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D013450:Sulfones / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation
C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D007155:Immunologic Factors; D016898:Interferon-alpha; D016328:NF-kappa B; D009570:Nitriles; D012333:RNA, Messenger; D013450:Sulfones; D051571:Protein Kinase C-alpha