Early NF-κB activation is associated with hormone-induced pancreatitis

Inflammation and cell death are critical to pathogenesis of acute pancreatitis. Here we show that transcription factor nuclear factor-kappa B (NF-kappa B), which regulates these processes, is activated and plays a role in rat cerulein pancreatitis. NF-kappa B was strongly activated in the pancreas within 30 min of cerulein infusion; a second phase of NF-kappa B activation was prominent at 3-6 h. This biphasic kinetics could result from observed transient degradation of the inhibitory protein I kappa B alpha and slower but sustained degradation of I kappa B beta. The hormone also caused NF-kappa B translocation and I kappa B degradation in vitro in dispersed pancreatic acini. Both p65/p50 and p50/p50, but not c-Rel, NF-kappa B complexes were manifest in pancreatitis and in isolated acini. Coinfusion of CCK JMV-180, which abolishes pancreatitis, prevented cerulein-induced NF-kappa B activation. The second but not early phase of NF-kappa B activation was inhibited by a neutralizing tumor necrosis factor-alpha antibody. Antioxidant N-acetylcysteine (NAC) blocked NF-kappa B activation and significantly improved parameters of pancreatitis. In particular, NAC inhibited intrapancreatic trypsin activation and mRNA expression of cytokines interleukin-6 and KC, which were dramatically induced by cerulein. The results suggest that NF-kappa B activation is an important early event that may contribute to inflammatory and cell death responses in acute pancreatitis.