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This Article Full Text Full Text (PDF) All Versions of this Article: 289/4/L536    most recent 00164.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Citing Articles Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Mora, A. L. Articles by Rojas, M. Search for Related Content PubMed PubMed Citation Articles by Mora, A. L. Articles by Rojas, M.

Prevention of NF-B activation in vivo by a cell-permeable NF-B inhibitor peptide

¹Division of Pulmonary, Allergy, and Critical Care Medicine, ²Center for Translational Research in the Lung, and ³McKelvey Center for Lung Transplantation, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia; and ⁴Department of Medicine, Vanderbilt University, Nashville, Tennessee

Submitted 12 April 2005 ; accepted in final form 6 June 2005

The NF-B/Rel transcription factor family plays a central role in coordinating the expression of a variety of genes that regulate stress responses, immune cell activation, apoptosis, proliferation, differentiation, and oncogenic transformation. Interventions that target the NF-B pathway may be therapeutic for a variety of pathologies, especially immune/inflammatory diseases. Using membrane translocating sequence (MTS) technology, we developed a cell-permeable dominant inhibitor of NF-B activation, termed IB-(N)-MTS. This molecule contains a 12-amino acid MTS motif attached to the COOH-terminal region of a nondegradable inhibitor protein [IB-(N)]. The recombinant protein enters cells and localizes in the cytoplasm. Delivery of the IB-(N)-MTS to cell lines and primary cells inhibited nuclear translocation of NF-B proteins induced by cell activation. The protein also effectively inhibited NF-B activation in vivo in two different animal models: NF-B activation in response to skin wounding in mice and NF-B activation in lungs after endotoxin treatment in sheep. Inhibition of NF-B by the IB-(N)-MTS in the endotoxin model attenuated physiological responses to endotoxemia. These data demonstrate that activation of NF-B can be inhibited using a recombinant protein designed to penetrate into cells. This technology may provide a new approach to NF-B pathway-targeted therapies.

drug delivery; therapy; cell-permeable protein; inflammation; lung injury