UP-REGULATION OF TNF-ALPHA MESSENGER-RNA IN THE RAT SPLEEN FOLLOWING INDUCTION OF ACUTE-PANCREATITIS

Tumor necrosis factor-alpha (TNF alpha) is postulated to be a mediator of the systemic complications associated with acute pancreatitis, Neu tralization of TNF alpha with monoclonal antibody ameliorates the morb idity and mortality associated with acute pancreatitis in a rat model. Although high levels of TNF alpha are measurable in peripheral blood in acute pancreatitis, specific sites of TNF alpha production in this disease have not been described. In this study we show that induction of pancreatitis causes up-regulation of TNF alpha messenger RNA (mRNA) at a distant organ site, the spleen. Hemisplenectomies were performed in male Sprague-Dawley rats prior to induction of pancreatitis by pan creatic duct infusion of artificial bile, Completion hemisplenectomies were then performed at 30 min, 1 hr, and 2 hr after pancreatitis indu ction, Quantitation of TNF alpha mRNA in the hemispleens before and af ter pancreatitis using a semiquantitative reverse transcriptase-polyme rase chain reaction method revealed an 80-fold increase in amount of T NF alpha mRNA by 2 hr after induction of pancreatitis. By contrast, co ntrol rats receiving a sham operation showed no significant increase i n TNF alpha mRNA expression after infusion of the pancreatic duct with saline. The increase in TNF alpha mRNA production was associated with increased serum TNF alpha product levels and was independent of endot oxin. We conclude that severe acute pancreatitis in the rat model is a ssociated with significant up-regulation of TNF alpha mRNA in splenic mononuclear cells. These data provide evidence that the local events o f acute pancreatitis can induce up-regulation of TNF alpha mRNA at a d istant site and suggest a possible mechanism of pathogenesis of the sy stemic manifestations of this disease. (C) 1995 Academic Press, Inc.