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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-kappaB 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-kappaB, when assessed by electromobility shift assay, immunoblotting, and immunofluorescence for p65. This correlated with inhibition of both C. rodentium-stimulated IkappaB-alpha phosphorylation and degradation, and IkappaB kinase activity, which occurred by inhibition of IkappaB 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-kappaB-driven proinflammatory epithelial responses to pathogenic colonic bacteria.