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B Kinase Inhibitor NEMO Binding Domain Peptide1
,¶
* Department of Medicine,
Department of Immunology, and
Department of Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261;
Department of Medicine and
¶ Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC 27599;
|| Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104;
# Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599; and
** Theralogics Inc., Chapel Hill, NC 27599
The NF-
B family of transcription factors is a central regulator of chronic inflammation. The phosphorylation of IB proteins by the IB kinase (IKK) complex (IKK
, IKKβ, and NF-B essential modulator or NEMO) is a key step in NF-B activation. Peptides corresponding to the NEMO binding domain (NBD) of IKK blocks NF-B activation without inhibiting basal NF-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-B reporter system, 8K-NBD dose-dependently inhibits TNF-induced NF-B activation. Furthermore, 8K-NBD inhibited nuclear translocation of NF-B family members. In NF-BEGFP knock-in mice, 8K-NBD inhibited LPS-activated NF-B (EGFP activity) in the ileum but did not inhibit basal NF-B in Peyer’s patches. IL-10–/– mice treated systemically with 8K-NBD demonstrate amelioration of established colitis, decreased NF-B activation in the lamina propria, and a reduction in spontaneous intestinal IL-12 p40, TNF, IFN-
, 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants AI35098 (to A.S.B.), R01 DK54452, R41 DK074193 (to S.E.P.), and P30 DK34987 (to S.E.P. and C.J.), National Research Service Award F30 ES013617 (to S.H.D.), and funding from the Broad Medical Research Program (to S.E.P.).
2 S.H.D. and J.S.T. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Scott E. Plevy, University of North Carolina at Chapel Hill School of Medicine, Division of Gastroenterology and Hepatology, 103 Mason Farm Road, Campus Box 7032, 7341C MBRB, Chapel Hill, NC 27599-7032. E-mail address: scott_plevy{at}med.unc.edu
4 Abbreviations used in this paper: IBD, inflammatory bowel disease; BM, bone marrow; CD, Crohn’s disease; 6CF, 6-carboxyfluorescein; DC, dendritic cell; DSS, dextran sulfate sodium; EGFP, enhanced GFP; IKK, IB kinase; mNBD, mutant NBD; NBD, NEMO binding domain; NEMO, NF-B essential modulator; phospho, phosphorylated; PTD, protein transduction domain; TNBS, trinitrobenzene sulfonic acid.
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