Caerulein-induced NF-κB/Rel activation requires both Ca2+ and protein kinase 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 during the course of caerulein pancreatitis. Here, we show that activation of NF-kappa B/Rel by caerulein, a CCK analog, requires increasing intracellular Ca2+ levels and protein kinase C activation. Caerulein induces a dose-dependent 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 beta was only slightly affected by caerulein treatment. Consistent with an involvement of Ca2+, the endoplasmic reticulum-resident Ca2+-ATPase inhibitor thapsigargin activated NF-kappa B/Rel in pancreatic lobules. The intracellular Ca2+ chelator TMB-8 prevented I kappa B alpha degradation and subsequent nuclear translocation of NF-kappa B/Rel induced by caerulein. BAPTA-AM was less effective. Cyclosporin A, a Ca2+/calmodulin-dependent protein phosphatase (PP2B) inhibitor, decreased caerulein-induced NF-kappa B/Rel activation and I kappa B alpha degradation. The inhibitory effect of bisindolylmaleimide suggests that protein kinase C activity is also required for caerulein-induced NF-kappa B/ Rel activation. These data suggest that Ca2+- as well as protein kinase C-dependent mechanisms are required for caerulein-induced NF-kappa B/Rel activation.