title: Requirement of c-Jun NH2-terminal kinase activation in interferon-alpha-induced apoptosis through upregulation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in Daudi B lymphoma cells.
abstract: Interferon alpha (IFN-alpha) inhibits growth, at least in part, through induction of apoptosis. However, the molecular mechanisms underlying IFN-alpha-induced apoptosis are not completely understood. In the present study, we found that IFN-alpha induced a sustained activation of c-Jun N-terminal kinase 1 (JNK1), but not extracellular kinases (ERKs), in Daudi B lymphoma cells, as assessed by Western blotting using phospho-specific antibodies. Several lines of evidence support the notion that the IFN-alpha-induced activation of JNK is responsible for IFN-alpha-induced apoptosis, at least in part, through upregulation of TNF-related apoptosis-inducing ligand (TRAIL). First, pretreatment of Daudi cells with a JNK inhibitor reduced IFN-alpha-induced upregulation of TRAIL and loss of mitochondrial membrane potential (DeltaPsim) and annexin-positive cells, which was assessed by flow cytometry. Second, a dominant-negative form of JNK1 (dnJNK1) also reduced these apoptotic events, while a constitutively active form of JNK1, MKK7-JNK1beta, enhanced them. Finally, treatment with IFN-alpha enhanced the promoter activity of the TRAIL gene, which was partially abrogated by either JNK inhibitor or dnJNK1, while it was moderately enhanced by MKK7-JNK1beta. These findings are useful for understanding molecular mechanisms of IFN-alpha-induced apoptosis and also for development of treatment modalities of some tumors with IFN-alpha.
authors.affiliation: Department of Immunology and Intractable Immunology 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: Kikumi
authors.initials: K
authors.lastname: Hata
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Shimo
authors.forename: Miho
authors.initials: M
authors.lastname: Hayashida
authors.forename: B Mark
authors.initials: BM
authors.lastname: Evers
authors.forename: Junichiro
authors.initials: J
authors.lastname: Mizuguchi
mesh_terms: D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000187:drug effects; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000235:genetics*; D033681:Mitochondrial Membrane Transport Proteins / Q000502:physiology; D011401:Promoter Regions, Genetic; D053221:TNF-Related Apoptosis-Inducing Ligand; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D033681:Mitochondrial Membrane Transport Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D048031:JNK Mitogen-Activated Protein Kinases