Acute pancreatitis-induced enzyme release and necrosis are attenuated by IL-1 antagonism through an indirect mechanism.
Interleukin-1 beta (IL-1) is a proinflammatory cytokine which is produced within the pancreas during acute pancreatitis reaching levels which are toxic to many cell types. Since antagonism of this cytokine provides dramatic survival benefits during lethal pancreatitis, we hypothesized that IL-1 had direct secretagogue and cytolytic effects within the pancreas. The effect of IL-1 on pancreatic exocrine function and tissue viability was assessed in vivo by blockade of IL-1 with varying doses of IL-1 receptor antagonist (IL-1ra) prior to the induction of either moderate (caerulein-induced) or severe (choline deficient diet-induced) necrotizing pancreatitis. Subsequent in vitro studies were conducted to determine the direct effect of IL-1 on dispersed rat acini prepared through collagenase digestion. Amylase release was measured after a 30-min incubation with varying doses of recombinant IL-1 beta. Viability was determined in the presence of IL-1 via trypan blue exclusion at multiple time points. Blockade of the IL-1 receptor decreased pancreatic amylase release and tissue necrosis in both models of pancreatitis in a dose-dependent fashion (1.0 mg/kg, P = NS; 10 mg/kg, P < 0.05; 100 mg/kg, P < 0.05). Despite these in vivo findings, the addition of IL-1 to acini in vitro had no effect on exocrine function and failed to decrease acini viability (both, P = NS). Pancreatic amylase release and tissue necrosis are significantly attenuated during experimental pancreatitis by IL-1 antagonism. These changes do not appear to be due to the direct action of IL-1 on pancreatic acini and are likely due to more complex interactions between acini and cytokine-producing leukocytes.
Fink
G
G
Department of Surgery, University of South Florida, Tampa, USA.
Yang
J
J
Carter
G
G
Norman
J
J
D000208:Acute Disease; D000681:Amylases / Q000097:blood* / Q000187:drug effects; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002108:Ceruletide / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005088:Exocrine Glands / Q000187:drug effects; D007375:Interleukin-1 / Q000502:physiology*; D008297:Male; D051379:Mice; D009336:Necrosis; D010195:Pancreatitis / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology*; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins / Q000494:pharmacology
D007375:Interleukin-1; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D002108:Ceruletide; D000681:Amylases