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

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