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

Shaival H. Davé, Jeremy S. Tilstra, Katsuyoshi Matsuoka, Fengling Li, Thomas Karrasch, Jennifer K. Uno, Antonia R. Sepulveda, Christian Jobin, Albert S. Baldwin, Paul D. Robbins, Scott E. Plevy

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Abstract

The NF-κB family of transcription factors is a central regulator of chronic inflammation. The phosphorylation of IκB proteins by the IκB kinase (IKK) complex (IKKα, IKKβ, and NF-κB essential modulator or NEMO) is a key step in NF-κB activation. Peptides corresponding to the NEMO binding domain (NBD) of IKK blocks NF-κB activation without inhibiting basal NF-κB 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-κB reporter system, 8K-NBD dose-dependently inhibits TNF-induced NF-κB activation. Furthermore, 8K-NBD inhibited nuclear translocation of NF-κB family members. In NF-κBEGFP knock-in mice, 8K-NBD inhibited LPS-activated NF-κB (EGFP activity) in the ileum but did not inhibit basal NF-κB in Peyer's patches. IL-10-/- mice treated systemically with 8K-NBD demonstrate amelioration of established colitis, decreased NF-κB activation in the lamina propria, and a reduction in spontaneous intestinal IL-12 p40, TNF, IFN-γ, 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.

Original languageEnglish
Pages (from-to)7852-7859
Number of pages8
JournalJournal of Immunology
Volume179
Issue number11
Publication statusPublished - 2007 Dec 1

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Colitis
Phosphotransferases
Peptides
Interleukin-10
Peyer's Patches
Interleukin-17
Interleukin-12
Ileum
Inflammatory Bowel Diseases
Protein Kinases
Lysine
Mucous Membrane
Transcription Factors
Phosphorylation
Inflammation
Protein Domains
Therapeutics

ASJC Scopus subject areas

  • Immunology

Cite this

Davé, S. H., Tilstra, J. S., Matsuoka, K., Li, F., Karrasch, T., Uno, J. K., ... Plevy, S. E. (2007). Amelioration of chronic murine colitis by peptide-mediated transduction of the IκB kinase inhibitor NEMO binding domain peptide. Journal of Immunology, 179(11), 7852-7859.

Amelioration of chronic murine colitis by peptide-mediated transduction of the IκB kinase inhibitor NEMO binding domain peptide. / Davé, Shaival H.; Tilstra, Jeremy S.; Matsuoka, Katsuyoshi; Li, Fengling; Karrasch, Thomas; Uno, Jennifer K.; Sepulveda, Antonia R.; Jobin, Christian; Baldwin, Albert S.; Robbins, Paul D.; Plevy, Scott E.

In: Journal of Immunology, Vol. 179, No. 11, 01.12.2007, p. 7852-7859.

Research output: Contribution to journalArticle

Davé, SH, Tilstra, JS, Matsuoka, K, Li, F, Karrasch, T, Uno, JK, Sepulveda, AR, Jobin, C, Baldwin, AS, Robbins, PD & Plevy, SE 2007, 'Amelioration of chronic murine colitis by peptide-mediated transduction of the IκB kinase inhibitor NEMO binding domain peptide', Journal of Immunology, vol. 179, no. 11, pp. 7852-7859.
Davé, Shaival H. ; Tilstra, Jeremy S. ; Matsuoka, Katsuyoshi ; Li, Fengling ; Karrasch, Thomas ; Uno, Jennifer K. ; Sepulveda, Antonia R. ; Jobin, Christian ; Baldwin, Albert S. ; Robbins, Paul D. ; Plevy, Scott E. / Amelioration of chronic murine colitis by peptide-mediated transduction of the IκB kinase inhibitor NEMO binding domain peptide. In: Journal of Immunology. 2007 ; Vol. 179, No. 11. pp. 7852-7859.
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AU - Li, Fengling

AU - Karrasch, Thomas

AU - Uno, Jennifer K.

AU - Sepulveda, Antonia R.

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