Amelioration of Chronic Murine Colitis by Peptide-Mediated Transduction of the IκB Kinase Inhibitor NEMO Binding Domain Peptide1

• 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
• ISSN: 0022-1767; 1550-6606

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