Amelioration of chronic murine colitis by peptide-mediated transduction of the IkappaB kinase inhibitor NEMO binding domain peptide.
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.
Davé
Shaival H
SH
Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Tilstra
Jeremy S
JS
Matsuoka
Katsuyoshi
K
Li
Fengling
F
Karrasch
Thomas
T
Uno
Jennifer K
JK
Sepulveda
Antonia R
AR
Jobin
Christian
C
Baldwin
Albert S
AS
Robbins
Paul D
PD
Plevy
Scott E
SE
D000818:Animals; D002460:Cell Line; D002908:Chronic Disease; D003092:Colitis / Q000188:drug therapy* / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors / Q000276:immunology; D016753:Interleukin-10 / Q000172:deficiency / Q000276:immunology; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008239:Lysine / Q000031:analogs & derivatives / Q000276:immunology / Q000627:therapeutic use; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000276:immunology; D010455:Peptides / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D015398:Signal Transduction / Q000276:immunology*; D014161:Transduction, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology
D008070:Lipopolysaccharides; C467063:NBD peptide, mouse; D016328:NF-kappa B; D010455:Peptides; D047428:Protein Kinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D051550:I-kappa B Kinase; D008239:Lysine