Interleukin-1 beta (IL-1 beta) is produced in large amounts during
acute pancreatitis and is believed to play a role in
disease progression. Because secretion of
IL-1 beta is dependent on intracellular processing of pro-IL-1 beta by
IL-1 converting
enzyme (
ICE), we aimed to determine 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 receive
VE-13045 or vehicle before induction of
pancreatitis. To confirm our findings and to ensure that the results were not model dependent, a second series of experiments was conducted using mice possessing a homozygous knockout of the
ICE gene in which lethal
pancreatitis was induced 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 mRNA induction was assessed by differential RT-PCR.
Acute pancreatitis was associated with a 120-fold increase in
IL-1 beta mRNA, which was not affected by
ICE inhibition or gene deletion.
Cytokine processing and secretion were affected, as evidenced by decreased serum levels of
IL-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 groups 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 secretion of proinflammatory
cytokines without altering
IL-1 mRNA production and is associated with decreased
pancreatitis severity and dramatic survival benefits.