title: Balance between NF-kappaB and JNK/AP-1 activity controls dendritic cell life and death.
abstract: The life cycle of dendritic cells (DCs) must be precisely regulated for proper functioning of adaptive immunity. However, signaling pathways actively mediating DC death remain enigmatic. Here we describe a novel mechanism of hierarchical transcriptional control of DC life and death. Ligation of tumor necrosis factor receptor superfamily (TNFR-SF) members on DCs and cognate contact with T cells resulted in quantitatively balanced nuclear factor-kappaB (NF-kappaB) and c-Jun N-terminal kinase (JNK)-mediated activator protein-1 (AP-1) induction and strongly enhanced DC longevity. Specific blockade of NF-kappaB in DCs induced strongly augmented JNK/AP-1 activity because of elevated levels of reactive oxygen species. In this scenario, DC activation by TNFR-SF members or T cells induced DC apoptosis. Specific inhibition of JNK/AP-1 rescued DCs from this activation-induced cell death program and restored TNFR-SF member- and T-cell-mediated survival. We conclude that JNK/AP-1 activity is under negative feedback control of NF-kappaB and can execute apoptosis in DCs. Thus, feedback-controlled signaling amplitudes of 2 transcriptional pathways decide the fate of a DC.
authors.affiliation: Department of Dermatology, Division of Immunology, Allergy and Infectious Diseases, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
authors.forename: Ernst
authors.initials: E
authors.lastname: Kriehuber
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Bauer
authors.forename: Anne-Sophie
authors.initials: AS
authors.lastname: Charbonnier
authors.forename: Dorian
authors.initials: D
authors.lastname: Winter
authors.forename: Stefan
authors.initials: S
authors.lastname: Amatschek
authors.forename: Dietmar
authors.initials: D
authors.lastname: Tamandl
authors.forename: Norbert
authors.initials: N
authors.lastname: Schweifer
authors.forename: Georg
authors.initials: G
authors.lastname: Stingl
authors.forename: Dieter
authors.initials: D
authors.lastname: Maurer
mesh_terms: D019013:CD40 Antigens / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D016923:Cell Death / Q000276:immunology; D002478:Cells, Cultured; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology* / Q000378:metabolism*; D000078404:Epidermal Cells; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D007801:Langerhans Cells / Q000166:cytology / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D018384:Oxidative Stress / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation / Q000276:immunology; D014162:Transfection
chemical_list: D019013:CD40 Antigens; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D018808:Transcription Factor AP-1; D000072000:NF-KappaB Inhibitor alpha; D048031:JNK Mitogen-Activated Protein Kinases