[HTML][HTML] MC-12, an annexin A1-based peptide, is effective in the treatment of experimental colitis

N Ouyang, C Zhu, D Zhou, T Nie, MF Go, RJ Richards… - PLoS …, 2012 - journals.plos.org
N Ouyang, C Zhu, D Zhou, T Nie, MF Go, RJ Richards, B Rigas
PLoS One, 2012journals.plos.org
Annexin A1 (ANXA1) inhibits NF-κB, a key regulator of inflammation, the common
pathophysiological mechanism of inflammatory bowel diseases (IBD). MC-12, an ANXA1-
based tripeptide, suppresses NF-κB activation. Here, we determined the efficacy of MC-12 in
the control of IBD. Mice with colitis induced by dextran sodium sulfate (DSS) or 2, 4, 6-trinitro
benzene sulfonic acid (TNBS) were treated with various doses of MC-12 administered
intraperitoneally, orally or intrarectally. We determined colon length and the histological …
Annexin A1 (ANXA1) inhibits NF-κB, a key regulator of inflammation, the common pathophysiological mechanism of inflammatory bowel diseases (IBD). MC-12, an ANXA1-based tripeptide, suppresses NF-κB activation. Here, we determined the efficacy of MC-12 in the control of IBD. Mice with colitis induced by dextran sodium sulfate (DSS) or 2,4,6-trinitro benzene sulfonic acid (TNBS) were treated with various doses of MC-12 administered intraperitoneally, orally or intrarectally. We determined colon length and the histological score of colitis, and assayed: in colon tissue the levels of TNF-α, IFN-γ, IL-1β, IL-6 and IL-10 by RT-PCR; prostaglandin E2 (PGE2), cytoplasmic phospholipase A2 (cPLA2) and myeloperoxidase by immunoassay; and COX-2 and NF- κB by immunohistochemistry; and in serum the levels of various cytokines by immunoassay. In both models MC-12: reversed dose-dependently colonic inflammation; inhibited by up to 47% myeloperoxidase activity; had a minimal effect on cytoplasmic phospholipase A2; reduced significantly the induced levels of TNF-α, IFN-γ, IL-1β, IL-6 and IL-10, returning them to baseline. DSS and TNBS markedly activated NF-κB in colonic epithelial cells and MC-12 decreased this effect by 85.8% and 72.5%, respectively. MC-12 had a similar effect in cultured NCM460 normal colon epithelial cells. Finally, MC-12 suppressed the induction of COX-2 expression, the level of PGE2 in the colon and PGE2 metabolite in serum. In conclusion, MC-12, representing a novel class of short peptide inhibitors of NF-κB, has a strong effect against colitis in two preclinical models recapitulating features of human IBD. Its mechanism of action is complex and includes pronounced inhibition of NF-κB. MC-12 merits further development as an agent for the control of IBD.
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