THERAPEUTIC MODIFICATION OF NUCLEAR FACTOR KAPPA-B BINDING-ACTIVITY AND TUMOR-NECROSIS-FACTOR-ALPHA GENE-EXPRESSION DURING ACUTE BILIARY PANCREATITIS

The role of cytokines has been well documented in the pathogenesis of acute pancreatitis. Antibodies against specific cytokines have been us ed to treat pancreatitis, with mixed results. The transcription factor nuclear factor (NF)-kappa B is a pleiotropic regulator of many genes involved in stress and inflammatory responses. The aim of this study w as to prevent the NF-kappa B binding activity and tumor necrosis facto r (TNF)-alpha gene overexpression as a possible therapeutic interventi on for acute pancreatitis. Reversible acute biliary pancreatitis was i nduced in male Sprague Dawley rats as established in this laboratory. The animals were sacrificed at 0, 5, 15, 30 min and 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours after the induction of pancreatitis. NF-kappa B b inding activity was determined by electrophoretic mobility shift assay , and TNF-alpha gene expression was assayed by reverse transcription-P CR. NF-kappa B binding activity was markedly higher around 4 hours and persisted up to 24 hours after pancreatitis induction in animals with acute pancreatitis, whereas TNF-alpha mRNA levels peaked at 24 hours. When amobarbital (to block NF-kappa B activation) was given (60 mg/kg body weight, I.P.) 3 hours before induction of pancreatitis, the acti vation of NF-kappa B and the overexpression of TNF-alpha gene was prev ented, with significantly decreased severity of pancreatitis as assess ed by amylase and clinical recovery. We conclude that 1) preventing th e activation of NF-kappa B eliminates the induced overexpression of in flammatory cytokines (TNF-alpha) in acute pancreatitis, 2) such interv ention correlates with clinical improvement in pancreatitis, and 3) th is genetic modification offers a possible therapeutic intervention in acute pancreatitis.