Inhibition of NF-κB activity in human T lymphocytes induces caspase- dependent apoptosis without detectable activation of caspase-1 and -3

Vladimir Kolenko, Tracy Bloom, Patricia Rayman, Ronald Bukowski, Eric Hsi, James Finke

Research output: Contribution to journalArticlepeer-review

100 Scopus citations

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 languageEnglish
Pages (from-to)590-598
Number of pages9
JournalJournal of Immunology
Volume163
Issue number2
DOIs
StatePublished - 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

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