Inhibition of NF-κB induces a switch from CD95L-dependent to CD95L-independent and JNK-mediated apoptosis in T cells.
NF-κB is a crucial transcription factor regulating apoptosis sensitivity and resistance. It has been shown that inhibition of NF-κB in T lymphocytes leads to sensitization towards apoptosis. The underlying molecular mechanism is not entirely understood. Therefore, we investigated T cell receptor (TCR) stimulated apoptosis in T cells in which NF-κB activity is blocked by an inhibitor or IκBα overexpression. We show that enhanced apoptosis upon TCR stimulation is caspase- and JNK-dependent, but independent of the CD95/CD95L system. Generation of reactive oxygen species (ROS) induced sustained JNK phosphorylation by inactivation of MAP kinase phosphatase 7 (MKP7). Sustained JNK activation causes upregulation of the pro-apototic protein BIM. Thus, inhibition of NF-κB causes a switch from classical activation-induced cell death (AICD) to CD95L-independent apoptosis.
Tumor Immunology Program, German Cancer Research Center (DFKZ), Im Neuenheimer Feld 280, Heidelberg, Germany. m.kiessling@dkfz.de
Michael K
MK
Kiessling
Björn
B
Linke
Markus
M
Brechmann
Dorothee
D
Süss
Peter H
PH
Krammer
Karsten
K
Gülow
D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D054637:Dual-Specificity Phosphatases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D053222:Fas Ligand Protein / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D015759:Ionomycin / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019169:Jurkat Cells; D008565:Membrane Proteins / Q000378:metabolism; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D053222:Fas Ligand Protein; D008565:Membrane Proteins; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D011948:Receptors, Antigen, T-Cell; D015759:Ionomycin; D051550:I-kappa B Kinase; D048031:JNK Mitogen-Activated Protein Kinases; D054639:Mitogen-Activated Protein Kinase Phosphatases; C439065:DUSP16 protein, human; D054637:Dual-Specificity Phosphatases