title: MC-12, an annexin A1-based peptide, is effective in the treatment of experimental colitis.
abstract: 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 E(2) (PGE(2)), cytoplasmic phospholipase A(2) (cPLA(2)) 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 A(2); 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 PGE(2) in the colon and PGE(2) 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.
authors: Department of Medicine, Stony Brook University, Stony Brook, New York, United States of America.
authors: Nengtai
authors: N
authors: Ouyang
authors: Caihua
authors: C
authors: Zhu
authors: Dingying
authors: D
authors: Zhou
authors: Ting
authors: T
authors: Nie
authors: Mae F
authors: MF
authors: Go
authors: Robert J
authors: RJ
authors: Richards
authors: Basil
authors: B
authors: Rigas
mesh_terms: D000818:Animals; D017305:Annexin A1 / Q000737:chemistry*; D002460:Cell Line; D003092:Colitis / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D054513:Group IV Phospholipases A2 / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009842:Oligopeptides / Q000009:adverse effects / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D009195:Peroxidase / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid / Q000494:pharmacology
chemical_list: D017305:Annexin A1; D016207:Cytokines; D016328:NF-kappa B; D009842:Oligopeptides; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate; D009195:Peroxidase; D051546:Cyclooxygenase 2; D054513:Group IV Phospholipases A2; D015232:Dinoprostone