Caerulein-induced NF-kappaB/Rel activation requires both Ca2+ and protein kinase C as messengers.
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.
Tando
Y
Y
Department of Medicine I, University of Ulm, 89070 Ulm, Germany.
Algül
H
H
Wagner
M
M
Weidenbach
H
H
Adler
G
G
Schmid
R M
RM
D000818:Animals; D002118:Calcium / Q000502:physiology*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D002108:Ceruletide / Q000494:pharmacology*; D002614:Chelating Agents / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D016328:NF-kappa B / Q000502:physiology*; D010179:Pancreas / Q000378:metabolism; D011493:Protein Kinase C / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D015290:Second Messenger Systems; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D051841:Transcription Factor RelB; D014157:Transcription Factors / Q000502:physiology*
D002614:Chelating Agents; D005765:Gastrointestinal Agents; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; C497595:Relb protein, rat; D014157:Transcription Factors; D051841:Transcription Factor RelB; D016572:Cyclosporine; D002108:Ceruletide; D011493:Protein Kinase C; D000252:Calcium-Transporting ATPases; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium