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Prepublished online as a Blood First Edition Paper on May 22, 2003; DOI 10.1182/blood-2002-09-2960. This Article Full Text (PDF) All Versions of this Article: 2002-09-2960v1 102/6/2259    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Choi, M. Articles by Kettritz, R. Search for Related Content PubMed PubMed Citation Articles by Choi, M. Articles by Kettritz, R. Social Bookmarking                   What's this? Submitted September 27, 2002 Accepted May 14, 2003 Inhibition of NF-B by a TAT-NEMO-binding domain peptide accelerates constitutive apoptosis and abrogates LPS-delayed neutrophil apoptosis Mira Choi, Susanne Rolle, Maren Wellner, M Cristina Cardoso, Claus Scheidereit, Friedrich C Luft, and Ralph Kettritz* HELIOS Klinikum - Berlin, Franz-Volhard-Clinic, Medical Faculty of the Charite, Humboldt University, Berlin, Germany Max-Delbrueck-Center, Berlin, Germany * Corresponding author; email: kettritz{at}fvk-berlin.de. Delivery of biologically active peptides into human polymorphonuclear neutrophils (PMN) has implications for studying cellular functions and may be therapeutically relevant. The transcription factor NF-B regulates the expression of multiple genes controlling inflammation, proliferation, and cell survival. PMN play a crucial role in first line defense. Targeting NF-B in these cells may promote apoptosis and therefore facilitate resolution of inflammation. We used an 11-aminoacid sequence NEMO binding domain (NBD) that selectively inhibits the IKK (NEMO) IKK interaction, preventing NF-B activation. An HIV-TAT sequence served as a highly effective transducing shuttle. We show that LPS, GM-CSF, and dexamethasone (DEX) significantly reduced apoptosis after 20 hours. LPS, but not GM-CSF or DEX activated NF-B as shown by IB degradation, NF-B DNA binding, and transcriptional activity. The TAT-NBD blocked LPS-induced NF-B activation and NF-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-B activity in PMN. This strategy may help controlling various cellular functions even in short-lived, transfection-resistant primary human cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? 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