Balance between NF-kappaB and JNK/AP-1 activity controls dendritic cell life and death.
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.
Kriehuber
Ernst
E
Department of Dermatology, Division of Immunology, Allergy and Infectious Diseases, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
Bauer
Wolfgang
W
Charbonnier
Anne-Sophie
AS
Winter
Dorian
D
Amatschek
Stefan
S
Tamandl
Dietmar
D
Schweifer
Norbert
N
Stingl
Georg
G
Maurer
Dieter
D
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
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