GENE TARGETING DEMONSTRATES ADDITIVE DETRIMENTAL EFFECTS OF INTERLEUKIN-1 AND TUMOR-NECROSIS-FACTOR DURING PANCREATITIS

Background & Aims: During severe pancreatitis, interleukin (IL)-1 beta and tumor necrosis factor (TNF)-alpha are produced in large quantitie s. The aim of this study was to determine whether either one plays a m ore dominant role and if their detrimental effects are additive. Metho ds: Necrotizing pancreatitis was induced in transgenic (-/-) knockout mice deficient in either IL-1 type 1 receptors, TNF type 1 receptors, or both IL-1 and TNF type 1 receptors. Wild-type mice served as contro ls. Mortality was assessed for 10 days. Additional animals were killed on days 0, 1, 2, 3, and 4 for determination of pancreatitis severity. Results: All three knockout groups showed decreased amylase and lipas e, histological score, serum IL-6, and mortality compared with wild-ty pe groups. Animals devoid of receptors for both cytokines showed impro ved survival and decreased IL-6 levels compared with those devoid of e ither IL-1 or INF receptors individually, yet they failed to show a fu rther decrease in pancreatitis severity. Conclusions: Preventing the a ctivity of IL-1 beta or TNF-alpha has a nearly identical beneficial ef fect on the severity and mortality of acute pancreatitis. Preventing t he activity of both cytokines concurrently has no additional effect on pancreatitis severity but further attenuates the systemic stress resp onse and is associated with an additional but modest decrease in morta lity.