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Am J Physiol Lung Cell Mol Physiol 289: L536-L544, 2005. First published June 10, 2005; doi:10.1152/ajplung.00164.2005
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Prevention of NF-{kappa}B activation in vivo by a cell-permeable NF-{kappa}B inhibitor peptide

Ana L. Mora,1,2,3 John LaVoy,1,2 Martha McKean,1,2 Arlene Stecenko,1,2,3 Kenneth L. Brigham,1,2,3 Richard Parker,1,2 and Mauricio Rojas1,2,4

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-{kappa}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-{kappa}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-{kappa}B activation, termed I{kappa}B{alpha}-({Delta}N)-MTS. This molecule contains a 12-amino acid MTS motif attached to the COOH-terminal region of a nondegradable inhibitor protein [I{kappa}B{alpha}-({Delta}N)]. The recombinant protein enters cells and localizes in the cytoplasm. Delivery of the I{kappa}B{alpha}-({Delta}N)-MTS to cell lines and primary cells inhibited nuclear translocation of NF-{kappa}B proteins induced by cell activation. The protein also effectively inhibited NF-{kappa}B activation in vivo in two different animal models: NF-{kappa}B activation in response to skin wounding in mice and NF-{kappa}B activation in lungs after endotoxin treatment in sheep. Inhibition of NF-{kappa}B by the I{kappa}B{alpha}-({Delta}N)-MTS in the endotoxin model attenuated physiological responses to endotoxemia. These data demonstrate that activation of NF-{kappa}B can be inhibited using a recombinant protein designed to penetrate into cells. This technology may provide a new approach to NF-{kappa}B pathway-targeted therapies.

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


Address for reprint requests and other correspondence: M. Rojas, Division of Pulmonary, Allergy, and Critical Care Medicine, Center for Translational Research of the Lung, Emory Univ. School of Medicine, Atlanta, GA 30322 (e-mail: mrojas{at}emory.edu)






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