Caerulein-induced NF-kappa B/Rel activation requires both Ca2+ and proteinkinase C as messengers

The eukaryotic transcription factor NF-kappa B/Rel is activated by a large variety of stimuli. We have recently shown that NF-kappa B/Rel is induced d uring the course of caerulein pancreatitis. Here, we show that activation o f NF-kappa B/Rel by caerulein, a CCK analog, requires increasing intracellu lar Ca2+ levels and protein kinase C activation. Caerulein induces a dose-d ependent increase of nuclear NF-kappa B/Rel binding activity in pancreatic lobules, which is paralleled by degradation of I kappa B alpha. I kappa B b eta was only slightly affected by caerulein treatment. Consistent with an i nvolvement of Ca2+, the endoplasmic reticulum-resident Ca2+-ATPase inhibito r thapsigargin activated NF-kappa B/Rel in pancreatic lobules. The intracel lular Ca2+ chelator TMB-8 prevented I kappa B alpha degradation and subsequ ent nuclear translocation of NF-kappa B/Rel induced by caerulein. BAPTA-AM was less effective. Cyclosporin A, a Ca2+/calmodulin-dependent protein phos phatase (PP2B) inhibitor, decreased caerulein-induced NF-kappa B/Rel activa tion and I kappa B alpha degradation. The inhibitory effect of bisindolylma leimide suggests that protein kinase C activity is also required for caerul ein-induced NF-kappa B/ Rel activation. These data suggest that Ca2+- as we ll as protein kinase C-dependent mechanisms are required for caerulein-indu ced NF-kappa B/Rel activation.