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J. Biol. Chem., Vol. 283, Issue 24, 16752-16761, June 13, 2008

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The Apolipoprotein E-mimetic Peptide COG112 Inhibits the Inflammatory Response to Citrobacter rodentium in Colonic Epithelial Cells by Preventing NF-B Activation^*

Kshipra Singh, Rupesh Chaturvedi, Mohammad Asim, Daniel P. Barry, Nuruddeen D. Lewis^¶1, Michael P. Vitek^||, and Keith T. Wilson^¶2

From the Department of Medicine, Division of Gastroenterology, and the ^¶Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, the Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee 37212, and ^||Cognosci, Inc., Research Triangle Park, North Carolina 27709

Inflammatory bowel disease arises from the interplay between luminal bacteria and the colonic mucosa. Targeted inhibition of pro-inflammatory pathways without global immunosuppression is highly desirable. Apolipoprotein (apo) E has immunomodulatory effects and synthetically derived apoE-mimetic peptides are beneficial in models of sepsis and neuroinflammation. Citrobacter rodentium is the rodent equivalent of enteropathogenic Escherichia coli, and it causes colitis in mice by colonizing the surface of colonic epithelial cells and inducing signaling events. We have reported that mice deficient in inducible nitric-oxide (NO) synthase (iNOS) have attenuated C. rodentium-induced colitis. We used young adult mouse colon (YAMC) cells that mimic primary colonic epithelial cells to study effects of an antennapedia-linked apoE-mimetic peptide, COG112, on C. rodentium-activated cells. COG112 significantly attenuated induction of NO production, and iNOS mRNA and protein expression, in a concentration-dependent manner. COG112 inhibited the C. rodentium-stimulated induction of iNOS and the CXC chemokines KC and MIP-2 to the same degree as the NF-B inhibitors MG132 or BAY 11-7082, and there was no additive effect when COG112 and these inhibitors were combined. COG112 significantly reduced nuclear translocation of NF-B, when assessed by electromobility shift assay, immunoblotting, and immunofluorescence for p65. This correlated with inhibition of both C. rodentium-stimulated IB- phosphorylation and degradation, and IB kinase activity, which occurred by inhibition of IB kinase complex formation rather than by a direct effect on the enzyme itself. These studies indicate that apoE-mimetic peptides may have novel therapeutic potential by inhibiting NF-B-driven proinflammatory epithelial responses to pathogenic colonic bacteria.

Received for publication, December 26, 2007 , and in revised form, April 7, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants R41 DK075161 (to K. T. W. and M. P. V.) and R01 DK053620 (to K. T. W.). This work was also supported by the Office of Medical Research, Dept. of Veterans Affairs (to K. T. W.). 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 Supported by National Institutes of Health Grant T32 CA009592.

² To whom correspondence should be addressed: Vanderbilt University School of Medicine, 1030C MRB IV, 2215B Garland Ave., Nashville, TN 37232. Tel.: 615-343-5675; Fax: 615-343-6229; E-mail: keith.wilson{at}vanderbilt.edu.

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