ACTIVE INTERLEUKIN-1 RECEPTOR REQUIRED FOR MAXIMAL PROGRESSION OF ACUTE-PANCREATITIS

Objective The authors' aim was to determine the requirement for an act ive interleukin (IL)-1 receptor during the development and progression oi acute pancreatitis. Summary of Background Data Interleukin-1 is a pro-inflammatory cytokine that has been shown to be produced during ac ute pancreatitis. Earlier animal studies of moderate and severe pancre atitis have shown that blockade of this powerful mediator is associate d with attenuated pancreatic destruction and dramatic increases in sur vival. The exact role played by IL-1 and the requirement for activatio n of its receptor in the initiation and progression of pancreatitis is unknown. Methods Conventional and IL-1 receptor ''knockout'' animals were used in parallel experiments of acute pancreatitis induced by int raperitoneal injection of cerulean (50 mu g/kg every 1 hour X 4). The conventional mouse strain had the IL-l receptor blocked prophylactical ly by means of a recombinant IL-1 receptor antagonist (10 mg/kg inject ed intraperitoneally every 2 hours). The second mouse strain was genet ically engineered by means of gene targeting in murine embryonic stem cells to be devoid of type 1 IL-1 receptor(IL-1 receptor knockout). An imals were killed at 0, 0.5, 1, 2, 4, and 8 hours, with the severity o f pancreatitis determined by serum amylase, lipase, and IL-6 levels an d blind histologic grading. Strain-specific controls were used for com parison. Results The genetic absence oi the IL-1 receptor or its pharm acologic blockade resulted in significantly attenuated pancreatic vacu olization, edema, necrosis, inflammation, and enzyme release. Serum IL -6, a marker of inflammation severity, was dramatically decreased in b oth groups. Conclusions Activation of the IL-1 receptor is not require d for the development of pancreatitis but apparently is necessary for the maximal propagation of pancreatic injury and its associated inflam mation.