NF-κB/Rel activation in cerulein pancreatitis

Background & Aims: Recent evidence suggests that a number of rapid signaling cascades are initiated during secretagogue-induced pancreatitis. However, little is known about the nuclear events. The aim of this study was to explore activation of the transcription factor NF-kappa B/Rel after supramaximal stimulation with the cholecystokinin analogue cerulein in the pancreas. Methods & Results: Nuclear appearance of NF-kappa B/Rel-binding activity was detectable 15 minutes after cerulein injection. The DNA-binding activity consisted of NF-kappa B1 p50, NF-kappa B2 p52, and RelA p65 as judged by supershift assays and Western blot analysis. The onset and termination of NF-kappa B/Rel activation correlated with the degradation and reappearance of I kappa B alpha. Cerulein in supramaximal but not in physiological doses activated NF-kappa B/Rel in vitro. After blocking of NF-kappa B/Rel activation with pyrrolidine dithiocarbamate, the degree of morphological alterations was more pronounced than in controls, serum amylase and lactate dehydrogenase levels were significantly increased, and messenger RNA levels of pancreatitis-associated protein were more strongly induced, reflecting a more severe degree of pancreatitis. Similar results were obtained when N-acetyl-L-cysteine was used as an inhibitor of NF-kappa B activation. Conclusions: These data show that NF-kappa B/Rel is rapidly activated during cerulein pancreatitis. This activation may induce a self-defending genetic program before the onset of cellular injury, which might prevent higher degrees of damage of pancreatic acinar cells after secretagogue hyperstimulation.