Current Drug Targets

Francis J. Castellino
Kleiderer-Pezold Professor of Biochemistry
Director, W.M. Keck Center for Transgene Research
Dean Emeritus, College of Science
230 Raclin-Carmichael Hall, University of Notre Dame
Notre Dame, IN 46556
USA

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Nuclear Factor Kappa B is a Promising Therapeutic Target in Inflammatory Lung Disease

Author(s): Gye Y. Park and John W. Christman

Affiliation: Department of Medicine,Section of Pulmonary, Critical Care, and Sleep Medicine, University ofIllinois, 840 South Wood Street Chicago IL 60612, USA.

Keywords: inhibitory kappa B kinases (IKK), phosphorylation, neutrophils, proinflammatory mediators, posttranslational modification

Abstract:

Nuclear factor kappa B (NF-kB) regulates the transcription of a wide array of gene products that are involved in the molecular pathobiology of the lung. Three lung cell types, epithelial cells, macrophages and neutrophils, have been shown to be involved in the generation of lung inflammation through signaling mechanisms that are dependent on activation of the NF-kB pathway. The basic molecular biology of the NF-kB activation pathway is well described, and approaches to modify this axis have involved inhibition of various components of the classical activation pathway, including ubiquitination and proteosomal degradation of IkB. Recently, there have been detailed characterizations of molecular mechanisms that involve reversible post-translational modification of RelA, including phosphorylation and acetylation that might be amenable to therapeutic interdiction. Alternately DNA decoy, antisense and siRNA technologies that interfere with NF-kB binding and inhibition of gene expression, respectively, of NF-kB proteins have been employed in experimental settings, but this has not been practically or effectively applied in human disease. A very promising approach, in our view, is inhibition of inhibitory kappa B kinases (IKK) since these appear to be highly specific for the NF-kB activation pathway and amenable to conventional small molecule pharmaceutical approaches.

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Article Details

VOLUME: 7
ISSUE: 6
Page: [661 - 668]
Pages: 8
DOI: 10.2174/138945006777435317