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

Abstract

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

Extracellular Signal-Regulated Kinase 1/2 and c-Jun NH2-Terminal Kinase, through Nuclear Factor-κB and Activator Protein-1, Contribute to Caerulein-Induced Expression of Substance P and Neurokinin-1 Receptors in Pancreatic Acinar Cells

“…Intracellular signaling molecules such as the MAPKs, cAMP, protein kinase C, and NF-B are known to be activated upon induction of acute pancreatitis (Tando et al, 1999;Lu et al, 2003;Bi and Williams, 2004;Thrower et al, 2008). Previous studies showed that activation of ERK1/2 and JNK induced cytokine production, and inhibition of ERK1/2 and JNK showed protective effects (Samuel et al, 2006(Samuel et al, , 2008Namkung et al, 2008).…”

Activation of the Adenosine A3Receptor in RAW 264.7 Cells Inhibits Lipopolysaccharide-Stimulated Tumor Necrosis Factor-α Release by Reducing Calcium-Dependent Activation of Nuclear Factor-κB and Extracellular Signal-Regulated Kinase 1/2

“…Furthermore, increase in intracellular Ca 2ϩ subsequent to glutamate receptor activation promotes NF-B activation (Mattson and Camandola, 2001). In addition, Ca 2ϩ , along with protein kinase C, has also been implicated in the activation of the NF-B in pancreatic lobules by the cholecystokinin analog caerulein (Tando et al, 1999). One mechanism by which elevated intracellular Ca 2ϩ couples to NF-B activation seems unique.…”

“…Studies in dendritic cells showed that LPSstimulated NF-B activation is mediated by a Ca 2ϩ -dependent and cyclosporin A-sensitive pathway, implicating the phosphatase calcineurin in the activation process (Lyakh et al, 2000). Furthermore, activation of NF-B in pancreatic lobules by the caerulein, a cholecystokinin analog (Tando et al, 1999), is also inhibited by cyclosporin A. Thus, it is possible that inhibition of intracellular Ca 2ϩ release and calcineurin could account for the reduction in LPS-mediated activation of NF-B by the A 3 AR.…”

From Calcium to NF-κB Signaling Pathways in Neurons

“…6), our results show a down-regulation of NF-B-mediated transcriptional activation. A variety of extracellular stimuli known to activate PKC also activate NF-B (8,9,33,49,50,68,85,94). Recently, it has also been suggested that PKC␣ as well as the atypical PKCs bind to the IKKs in vitro and in vivo and stimulate the activity of IKK␤ but not that of IKK␣ (47).…”