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

• Published in: The Journal of immunology (1950) 2007-12, Vol.179 (11), p.7852-7859
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Cell Line; Chronic Disease; Colitis - drug therapy; Colitis - immunology; Disease Models, Animal; Female; I-kappa B Kinase - antagonists & inhibitors; I-kappa B Kinase - immunology; Interleukin-10 - deficiency; Interleukin-10 - immunology; Lipopolysaccharides - antagonists & inhibitors; Lipopolysaccharides - pharmacology; Lysine - analogs & derivatives; Lysine - immunology; Lysine - therapeutic use; Macrophages - drug effects; Macrophages - immunology; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B - antagonists & inhibitors; NF-kappa B - immunology; Peptides - immunology; Peptides - pharmacology; Peptides - therapeutic use; Protein Kinase Inhibitors - immunology; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Signal Transduction - immunology; Transduction, Genetic; Tumor Necrosis Factor-alpha - antagonists & inhibitors; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0022-1767

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.