title: PKC-δ mediates interferon-α-induced apoptosis through c-Jun NH₂-terminal kinase activation.
abstract: BACKGROUND
  Interferon-α (IFN-α) exerts an anti-tumor effect at least through induction of apoptosis in a variety of types including B lymphoma cells. We recently found that IFN-α induced a sustained activation of c-Jun NH₂-terminal kinase1 (JNK1), which is implicated in activation of the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) promoter. In the present study, we explored upstream component(s) of the prolonged IFN-α-initiated activation of JNK1.
  
  
  RESULTS
  IFN-α caused activation of PKC-δ in Daudi B lymphoma cells and myeloma U266 cells, as detected by Western blotting using a monoclonal antibody specific for the phosphorylated form of PKC-δ. The dominant-negative form of mutant PKC-δ (dnPKC-δ) reduced the IFN-α-induced JNK1 activation, TRAIL promoter activity, loss of mitochondrial membrane potential (ΔΨm), and increase in propidium iodide (PI) positive cells. The IFN-α-induced activation of JNK1 and the TRAIL promoter was also attenuated by the PKC-δ inhibitor rottlerin. Moreover, a constitutively active form of mutant PKC-δ enhanced the IFN-α-induced TRAIL promoter activity and loss of ΔΨm in Daudi B lymphoma cells. In addition, IFN-α-induced Ser727 phosphorylation of Stat1 was also abrogated by dnPKC-δ.
  
  
  CONCLUSIONS
  IFN-α induced JNK1 activation via PKC-δ, leading to upregulation of TRAIL. The interaction of the consequent enhanced TRAIL expression with TRAIL-receptor results in a loss of ΔΨm and increase in PI positive cells. The IFN-α-induced apoptotic events may also be affected by the Ser727-Stat1 induced by PKC-δ-mediated signaling component(s).
authors.affiliation: Department of Immunology and Intractable Immune System Disease Research Center, Tokyo Medical University, 6-1-1 Shinjuku, Shinjuku-ku, Tokyo 160-8402, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Yanase
authors.forename: Miho
authors.initials: M
authors.lastname: Hayashida
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kanetaka-Naka
authors.forename: Akinori
authors.initials: A
authors.lastname: Hoshika
authors.forename: Junichiro
authors.initials: J
authors.lastname: Mizuguchi
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D016393:Lymphoma, B-Cell / Q000201:enzymology* / Q000503:physiopathology; D011401:Promoter Regions, Genetic; D051745:Protein Kinase C-delta / Q000235:genetics / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism
chemical_list: D016898:Interferon-alpha; D053221:TNF-Related Apoptosis-Inducing Ligand; D051745:Protein Kinase C-delta; D048031:JNK Mitogen-Activated Protein Kinases