Journal of Biological Chemistry
Volume 286, Issue 5, 4 February 2011, Pages 3839-3850
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Molecular Bases of Disease
The Apolipoprotein E-Mimetic Peptide COG112 Inhibits NF-κB Signaling, Proinflammatory Cytokine Expression, and Disease Activity in Murine Models of Colitis*

https://doi.org/10.1074/jbc.M110.176719Get rights and content
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Inflammatory bowel disease (IBD), consisting of Crohn's disease and ulcerative colitis, is a source of substantial morbidity and remains difficult to treat. New strategies for beneficial anti-inflammatory therapies would be highly desirable. Apolipoprotein (apo) E has immunomodulatory effects and synthetically derived apoE-mimetic peptides are beneficial in models of sepsis and neuroinflammation. We have reported that the antennapedia-linked apoE-mimetic peptide COG112 inhibits the inflammatory response to the colitis-inducing pathogen Citrobacter rodentium in vitro by inhibiting NF-κB activation. We now determined the effect of COG112 in mouse models of colitis. Using C. rodentium as an infection model, and dextran sulfate sodium (DSS) as an injury model, mice were treated with COG112 by intraperitoneal injection. With C. rodentium, COG112 improved the clinical parameters of survival, body weight, colon weight, and histologic injury. With DSS, COG112 ameliorated the loss of body weight, reduction in colon length, and histologic injury, whether administered concurrently with induction of colitis, during induction plus recovery, or only during the recovery phase of disease. In both colitis models, COG112 inhibited colon tissue inducible nitric-oxide synthase (iNOS), KC, TNF-α, IFN-γ, and IL-17 mRNA expression, and reduced nuclear translocation of NF-κB, as determined by immunoblot and immunofluorescence confocal microscopy. IκB kinase (IKK) activity was also reduced, which is necessary for activation of the canonical NF-κB pathway. Isolated colonic epithelial cells exhibited marked attenuation of expression of iNOS and the CXC chemokines KC and MIP-2. These studies indicate that apoE-mimetic peptides such as COG112 are novel potential therapies for IBD.

Cytokine
Immunology
Inflammation
Innate Immunity
Intestine
NF-κB
Nitric-oxide Synthase
Colitis

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*

This work was supported, in whole or in part, by National Institutes of Health Grants R41DK075161 (to K. T. W. and M. P. V.), R01DK053620, R01AT004821, and 3R01AT004821S1 (to K. T. W.), P01CA028842 (to K. T. W.), F31GM083500 (to N. D. L), T32CA009592 (N. D. L.), T32DK007673 (D. P. B.), the Flow Cytometry Core, and the Cell Imaging Core of the Vanderbilt University Digestive Disease Research Center supported by National Institutes of Health Grant P30DK058404; and a Merit Review Grant from the Office of Medical Research, Dept. of Veterans Affairs (to K. T. W.).

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S5.