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Amelioration of chronic murine colitis by peptide-mediated transduction of the I kappa B kinase inhibitor NEMO binding domain peptide

Academic Article
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Overview

authors

  • Dave, S. H.
  • Tilstra, J. S.
  • Matsuoka, K.
  • Li, F. L.
  • Karrasch, T.
  • Uno, J. K.
  • Sepulveda, A. R.
  • Jobin, C.
  • Baldwin, A. S.
  • Robbins, Paul D.
  • Plevy, S. E.

publication date

  • December 2007

journal

  • Journal of Immunology  Journal

abstract

  • The NF-kappaB family of transcription factors is a central regulator of chronic inflammation. The phosphorylation of IkappaB proteins by the IkappaB kinase (IKK) complex (IKKalpha, IKKbeta, and NF-kappaB essential modulator or NEMO) is a key step in NF-kappaB activation. Peptides corresponding to the NEMO binding domain (NBD) of IKK blocks NF-kappaB activation without inhibiting basal NF-kappaB activity. In this report, we determined the effects of the IKK inhibitor peptide (NBD) in a model of spontaneously occurring chronic murine colitis, the IL-10-deficient (IL-10(-/-)) mouse. Using a novel cationic peptide transduction domain (PTD) consisting of eight lysine residues (8K), we were able to transduce the NBD peptide into cells and tissues. In a NF-kappaB reporter system, 8K-NBD dose-dependently inhibits TNF-induced NF-kappaB activation. Furthermore, 8K-NBD inhibited nuclear translocation of NF-kappaB family members. In NF-kappaB(EGFP) knock-in mice, 8K-NBD inhibited LPS-activated NF-kappaB (EGFP activity) in the ileum but did not inhibit basal NF-kappaB in Peyer's patches. IL-10(-/-) mice treated systemically with 8K-NBD demonstrate amelioration of established colitis, decreased NF-kappaB activation in the lamina propria, and a reduction in spontaneous intestinal IL-12 p40, TNF, IFN-gamma, and IL-17 production. These results demonstrate that inhibitors of IKK, in particular a PTD-NBD peptide, may be therapeutic in the treatment of inflammatory bowel disease.

subject areas

  • Animals
  • Cell Line
  • Chronic Disease
  • Colitis
  • Disease Models, Animal
  • Female
  • I-kappa B Kinase
  • Interleukin-10
  • Lipopolysaccharides
  • Lysine
  • Macrophages
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B
  • Peptides
  • Protein Kinase Inhibitors
  • Signal Transduction
  • Transduction, Genetic
  • Tumor Necrosis Factor-alpha
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Identity

PubMed Central ID

  • PMC3203537

International Standard Serial Number (ISSN)

  • 0022-1767

PubMed ID

  • 18025231
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Additional Document Info

start page

  • 7852

end page

  • 7859

volume

  • 179

issue

  • 11

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