NEUTRALIZING IL-10 REVERSES THE PROTECTION AGAINST ACUTE PANCREATITIS BY CRAMBENE

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Acute pancreatitis is a disease of variable severity in which some patients experience mild, self-limited attacks while others manifest a severe, highly morbid, and frequently lethal attack. It has earlier been shown that mild acute pancreatitis is associated with extensive apoptotic acinar cell death while severe acute pancreatitis involves extensive acinar cell necrosis but very little acinar cell apoptosis. We have earlier shown that induction of the pancreatic acinar cell apoptosis in vivo by crambene (1-cyano-2-hydroxy-3-butene - CHB), a plant nitrile, protects mice against acute necrotizing pancreatitis. In the current study, we report a role for IL-10, an anti-inflammatory mediator, as part of the mechanism by which acinar cell apoptosis induced by CHB protects against acute pancreatitis. Acute pancreatitis was induced in the mouse by administering hourly intraperitoneal injections of a supra maximally stimulating dose (50 μg/kg) of the cholecystokinin analog caerulein for 10 hours. Neutralizing monoclonal anti-IL-10 antibody (2.5 mg/kg) was administered either with or without crambene (70 mg/kg) 12 hours before the first caerulein injection. Severity of acute pancreatitis was evaluated by estimation of serum amylase, pancreatic myeloperoxidase (MPO), water content, MCP-1 level, and morphological examination. Apoptosis in pancreatic sections was visualized by the terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick-end labeling method. CHB administration to normal mice resulted in persistently increased IL-10 levels in pancreas from 18 to 48 hours. While the prophylactic treatment with crambene in the acute pancreatitis model significantly reduced the severity, as evidenced by a significant attenuation of hyperamylasemia, pancreatic edema and, pancreatic MCP-1 levels. Also there was histological evidence of diminished pancreatic injury. The biochemical effects were reversed by the administration of anti- IL-10 together with CHB. There was also was greatly reduced apoptosis and enhanced necrosis with inflammation in mice treated with anit-IL-10 and CHB together. Our study shows that IL-10 plays an important role in the protection against acute pancreatitis by CHB and suggests that anti-inflammatory pathways may be involved in the protective effect of acinar cell apoptosis against acute pancreatitis.