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

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Item Type:	Article
Title:	Inhibition of NF-κ B by a TAT-NEMO-binding domain peptide accelerates constitutive apoptosis and abrogates LPS-delayed neutrophil apoptosis
Creators Name:	Choi, M., Rolle, S., Wellner, M., Cardoso, M.C., Scheidereit, C., Luft, F.C. and Kettritz, R.
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-{kappa}B (NF-{kapp}B) regulates the expression of multiple genes controlling inflammation, proliferation, and cell survival. PMNs play a crucial role in first-line defense. Targeting NF-{kappa}B 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 IKK{gamma} (NEMO)/IKK{beta} interaction, preventing NF-{kappa}B 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-{kappa}B as shown by I{kappa}B{alpha} degradation, NF-{kappa}B DNA binding, and transcriptional activity. The TAT-NBD blocked LPS-induced NF-{kappa}B activation and NF-{kappa}B–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-{kappa}B activity in PMNs. This strategy may help in controlling various cellular functions even in short-lived, transfection-resistant primary human cells.
Keywords:	Apoptosis, Binding Sites, Dexamethasone, Glucocorticoids, Granulocyte-Macrophage Colony-Stimulating Factor, I-{kappa} B Kinase, Lipopolysaccharides, NF-{kappa} B, Neutrophils, Peptide Fragments, Protein-Serine-Threonine Kinases, tat Gene Products
Source:	Blood
ISSN:	0006-4971
Publisher:	American Society of Hematology
Volume:	102
Number:	6
Page Range:	2259-2267
Date:	15 September 2003
Official Publication:	https://doi.org/10.1182/blood-2002-09-2960
PubMed:	View item in PubMed

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