The apolipoprotein E-mimetic peptide COG112 inhibits NF-kappaB signaling, proinflammatory cytokine expression, and disease activity in murine models of colitis.
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.
Department of Medicine, Division of Gastroenterology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Kshipra
K
Singh
Rupesh
R
Chaturvedi
Daniel P
DP
Barry
Lori A
LA
Coburn
Mohammad
M
Asim
Nuruddeen D
ND
Lewis
M Blanca
MB
Piazuelo
M Kay
MK
Washington
Michael P
MP
Vitek
Keith T
KT
Wilson
D000818:Animals; D002478:Cells, Cultured; D044082:Citrobacter rodentium / Q000472:pathogenicity; D003106:Colon / Q000166:cytology; D016207:Cytokines / Q000037:antagonists & inhibitors*; D016264:Dextran Sulfate / Q000009:adverse effects; D004195:Disease Models, Animal; D015212:Inflammatory Bowel Diseases / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D010455:Peptides / Q000494:pharmacology* / Q000627:therapeutic use
C530207:COG112 peptide; D016207:Cytokines; D016328:NF-kappa B; D010455:Peptides; D016264:Dextran Sulfate