A novel anti-inflammatory peptide ameliorates the severity of cholecystokinin-induced acute pancreatitis

Background: A previous finding demonstrated that a cell-permeable peptide containing the nuclear localization sequence of the p50-NF-ęB1 subunit of NF-ęB inhibits the nuclear import of NF-ęB and suppresses systemic inflammatory responses in vivo. To enhance efficacy of the substance, we replaced the cell permeable motif with the more efficient cell transporter penetratin. In vitro Luciferase reporter gene assay with pNF-ęB-Luc (in LPS stimulated RAW 264.7 macrophages and TNF stimulated L929 fibroblasts) revealed that our newly designed peptide named PN50 could suppress transcription activity of NF-ęB.

Aim: To assess the effect of the NF-ęB inhibitory peptide PN50 in an experimental model of acute pancreatitis (AP).

Methods: Pancreatitis was induced in male Wistar rats by administering 2×100 microg/kg of cholecystokinin-octapeptide (CCK) intraperitone-ally at an interval of 1h. The animals were sacrificed 4h after the first injection of CCK.

Results: Both pre- and after treatment with PN50 (200 microg/animal ip 30min before or after the first dose of CCK) ameliorated many of the examined laboratory (the pancreatic weight/body weight ratio, the serum amylase activity, the pancreatic levels of TNF-á and IL-6, the degree of lipid peroxidation, the pancreatic and lung myeloperoxidase activity) and morphological parameters of the disease. According to the histologic findings, treatment with PN50 protected the animals against AP by favoring induction of apoptotic, as opposed to the necrotic acinar cell death associated with severe AP.

Conclusion: Our study implies that reversible inhibitors of the nuclear import of stress-responsive transcription factors like NF-ęB might be clinically useful for the suppression of severity of AP.