SEVERITY AND MORTALITY OF EXPERIMENTAL PANCREATITIS ARE DEPENDENT ON INTERLEUKIN-1 CONVERTING-ENZYME (ICE)

Interleukin-1 beta (IL-1 beta) is produced in large amounts during acu te pancreatitis and is believed to play a role in disease progression. Because secretion of IL-1 beta is dependent on intracellular processi ng of pro-IL-1 beta by IL-1 converting enzyme (ICE), we aimed to deter mine the efficacy of a novel ICE inactivator (VE-13045) in inhibiting secretion of active IL-1 beta in vivo and if the loss of ICE activity would affect the severity and mortality of experimental pancreatitis. Severe hemorrhagic pancreatitis was induced in adult rats by infusion of bile acid into the pancreatic duct. Animals were randomized to rece ive VE-13045 or vehicle before induction of pancreatitis. To confirm o ur findings and to ensure that the results were not model dependent, a second series of experiments was conducted using mice possessing a ho mozygous knockout of the ICE gene in which lethal pancreatitis was ind uced by feeding a choline-deficient, ethionine-supplemented diet. The severity of pancreatitis was assessed for both experiments by standard surrogate markers, blind histologic grading, and serum IL-1 beta and tumor necrosis factor-alpha (TNF-alpha) levels. Pancreatic IL-1 beta m RNA induction was assessed by differential RT-PCR. Acute pancreatitis was associated with a 120-fold increase in IL-1 beta mRNA, which was n ot affected by ICE inhibition or gene deletion. Cytokine processing an d secretion were affected, as evidenced by decreased serum levels of I L-1 beta and TNF-alpha (p < 0.001) in all animals with an inactive ICE enzyme. This lack of cytokine production increased survival from 32% to 78% following bile salt pancreatitis (p < 0.01) and from 24% to 80% following diet-induced pancreatitis (p < 0.005). Both ICE-defective g roups demonstrated decreased pancreatic necrosis, edema, inflammation, wet weight (all p < 0.05), and amylase and lipase (p < 0.01), In vivo blockade or genetic deletion of ICE inhibits pancreatitis-induced sec retion of proinflammatory cytokines without altering IL-1 mRNA product ion and is associated with decreased pancreatitis severity and dramati c survival benefits.