Abstract
NF-κB is involved in the transcriptional control of various genes that act as extrinsic and intrinsic survival factors for T cells. Our findings show that suppression of NF-κB activity with cell-permeable SN50 peptide, which masks the nuclear localization sequence of NF-κB1 dimers and prevents their nuclear localization, induces apoptosis in resting normal human PBL. Inhibition of NF-κB resulted in the externalization of phosphatidylserine, induction of DNA breaks, and morphological changes consistent with apoptosis. DNA fragmentation was efficiently blocked by the caspase inbibitor Z-VAD-fmk and partially blocked by Ac-DEVD-fmk, suggesting that SN50-mediated apoptosis is caspase-dependent. Interestingly, apoptosis induced by NF-κB suppression, in contrast to that induced by TPEN (N,N,N',N'-tetrakis [2- pyridylmethyl]ethylenediamine) or soluble Fas ligand (CD95), was observed in the absence of active death effector proteases caspase-1-like (IL-1 converting enzyme), caspase-3-like (CPP32/Yama/apopain), and caspase-6-like and without cleavage of caspase-3 substrates poly(ADP-ribose) polymerase and DNA fragmentation factor-45. These findings suggest either low level of activation is required or that different caspases are involved. Preactivation of T cells resulting in NF-κB nuclear translocation protected cells from SN50-induced apoptosis. Our findings demonstrate an essential role of NF-κB in survival of naive PBL.
Original language | English |
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Pages (from-to) | 590-598 |
Number of pages | 9 |
Journal | Journal of Immunology |
Volume | 163 |
Issue number | 2 |
DOIs | |
State | Published - Jul 15 1999 |
Keywords
- Apoptosis/drug effects
- Caspase 1/metabolism
- Caspase 3
- Caspase 6
- Caspases/metabolism
- Cell Survival/drug effects
- Enzyme Activation/immunology
- Humans
- Immunosuppressive Agents/pharmacology
- Interphase/immunology
- Lymphocyte Activation/drug effects
- NF-kappa B/antagonists & inhibitors
- Peptides/physiology
- Phosphatidylserines/metabolism
- Protein Binding/drug effects
- T-Lymphocytes/cytology