Caerulein-induced NF-kappaB/Rel activation requires both Ca2+ and protein kinase C as messengers

Am J Physiol. 1999 Sep;277(3):G678-86. doi: 10.1152/ajpgi.1999.277.3.G678.


The eukaryotic transcription factor NF-kappaB/Rel is activated by a large variety of stimuli. We have recently shown that NF-kappaB/Rel is induced during the course of caerulein pancreatitis. Here, we show that activation of NF-kappaB/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-kappaB/Rel binding activity in pancreatic lobules, which is paralleled by degradation of IkappaBalpha. IkappaBbeta was only slightly affected by caerulein treatment. Consistent with an involvement of Ca2+, the endoplasmic reticulum-resident Ca2+-ATPase inhibitor thapsigargin activated NF-kappaB/Rel in pancreatic lobules. The intracellular Ca2+ chelator TMB-8 prevented IkappaBalpha degradation and subsequent nuclear translocation of NF-kappaB/Rel induced by caerulein. BAPTA-AM was less effective. Cyclosporin A, a Ca2+/calmodulin-dependent protein phosphatase (PP2B) inhibitor, decreased caerulein-induced NF-kappaB/Rel activation and IkappaBalpha degradation. The inhibitory effect of bisindolylmaleimide suggests that protein kinase C activity is also required for caerulein-induced NF-kappaB/Rel activation. These data suggest that Ca2+- as well as protein kinase C-dependent mechanisms are required for caerulein-induced NF-kappaB/Rel activation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / physiology*
  • Calcium-Transporting ATPases / antagonists & inhibitors
  • Ceruletide / pharmacology*
  • Chelating Agents / pharmacology
  • Cyclosporine / pharmacology
  • Dose-Response Relationship, Drug
  • Endoplasmic Reticulum / metabolism
  • Gastrointestinal Agents / pharmacology*
  • In Vitro Techniques
  • Male
  • NF-kappa B / physiology*
  • Pancreas / metabolism
  • Protein Kinase C / physiology*
  • Proto-Oncogene Proteins / physiology*
  • Rats
  • Rats, Wistar
  • Second Messenger Systems*
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transcription Factor RelB
  • Transcription Factors / physiology*


  • Chelating Agents
  • Gastrointestinal Agents
  • NF-kappa B
  • Proto-Oncogene Proteins
  • Relb protein, rat
  • Transcription Factors
  • Transcription Factor RelB
  • Cyclosporine
  • Ceruletide
  • Protein Kinase C
  • Calcium-Transporting ATPases
  • Tetradecanoylphorbol Acetate
  • Calcium