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Inhibition of NF-kappaB by a TAT-NEMO-binding domain peptide accelerates constitutive apoptosis and abrogates LPS-delayed neutrophil apoptosis.

Choi, Mira and Rolle, Susanne and Wellner, Maren and Cardoso, M Cristina and Scheidereit, Claus and Luft, Friedrich C. and Kettritz, Ralph (2003):
Inhibition of NF-kappaB by a TAT-NEMO-binding domain peptide accelerates constitutive apoptosis and abrogates LPS-delayed neutrophil apoptosis.
In: Blood, 102 (6), pp. 2259-67, ISSN 0006-4971,
[Online-Edition: http://www.cardoso-lab.org/publications/Choi_2003.pdf],
[Article]

Abstract

Delivery of biologically active peptides into human polymorphonuclear neutrophils (PMNs) has implications for studying cellular functions and may be therapeutically relevant. The transcription factor nuclear factor-kappaB (NF-kappaB) regulates the expression of multiple genes controlling inflammation, proliferation, and cell survival. PMNs play a crucial role in first-line defense. Targeting NF-kappaB in these cells may promote apoptosis and therefore facilitate resolution of inflammation. We used an 11-amino acid sequence NEMO-binding domain (NBD) that selectively inhibits the IKKgamma (NEMO)/IKKbeta interaction, preventing NF-kappaB activation. An HIV-TAT sequence served as a highly effective transducing shuttle. We show that lipopolysaccharide (LPS), granulocyte-macrophage colony-stimulating factor (GM-CSF), and dexamethasone (DEX) significantly reduced apoptosis after 20 hours. LPS, but not GM-CSF or DEX, activated NF-kappaB as shown by IkappaBalpha degradation, NF-kappaB DNA binding, and transcriptional activity. The TAT-NBD blocked LPS-induced NF-kappaB activation and NF-kappaB-dependent gene expression. TAT-NBD accelerated constitutive PMN apoptosis dose dependently and abrogated LPS-delayed apoptosis. These results provide a proof of principle for peptide delivery by TAT-derived protein transduction domains to specifically inhibit NF-kappaB activity in PMNs. This strategy may help in controlling various cellular functions even in short-lived, transfection-resistant primary human cells.

Item Type: Article
Erschienen: 2003
Creators: Choi, Mira and Rolle, Susanne and Wellner, Maren and Cardoso, M Cristina and Scheidereit, Claus and Luft, Friedrich C. and Kettritz, Ralph
Title: Inhibition of NF-kappaB by a TAT-NEMO-binding domain peptide accelerates constitutive apoptosis and abrogates LPS-delayed neutrophil apoptosis.
Language: German
Abstract:

Delivery of biologically active peptides into human polymorphonuclear neutrophils (PMNs) has implications for studying cellular functions and may be therapeutically relevant. The transcription factor nuclear factor-kappaB (NF-kappaB) regulates the expression of multiple genes controlling inflammation, proliferation, and cell survival. PMNs play a crucial role in first-line defense. Targeting NF-kappaB in these cells may promote apoptosis and therefore facilitate resolution of inflammation. We used an 11-amino acid sequence NEMO-binding domain (NBD) that selectively inhibits the IKKgamma (NEMO)/IKKbeta interaction, preventing NF-kappaB activation. An HIV-TAT sequence served as a highly effective transducing shuttle. We show that lipopolysaccharide (LPS), granulocyte-macrophage colony-stimulating factor (GM-CSF), and dexamethasone (DEX) significantly reduced apoptosis after 20 hours. LPS, but not GM-CSF or DEX, activated NF-kappaB as shown by IkappaBalpha degradation, NF-kappaB DNA binding, and transcriptional activity. The TAT-NBD blocked LPS-induced NF-kappaB activation and NF-kappaB-dependent gene expression. TAT-NBD accelerated constitutive PMN apoptosis dose dependently and abrogated LPS-delayed apoptosis. These results provide a proof of principle for peptide delivery by TAT-derived protein transduction domains to specifically inhibit NF-kappaB activity in PMNs. This strategy may help in controlling various cellular functions even in short-lived, transfection-resistant primary human cells.

Journal or Publication Title: Blood
Volume: 102
Number: 6
Divisions: 10 Department of Biology > Cell Biology and Epigenetics
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10 Department of Biology
Date Deposited: 06 Mar 2010 07:35
Official URL: http://www.cardoso-lab.org/publications/Choi_2003.pdf
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