CCK stimulatesmob-1 expression and NF-κB activation via protein kinase C and intracellular Ca2+

Abstract

Supraphysiological concentrations of cholecystokinin (CCK) induce chemokine expression in rat pancreatic acini through the activation of the transcription factor NF-κB. In the current study, the intracellular signals involved in these pathophysiological effects of CCK were investigated. CCK induction of mob-1 expression in isolated rat pancreatic acini was blocked by the protein kinase C (PKC) inhibitors GF-109203X and Ro-32–0432 and by the intracellular Ca2+chelator BAPTA. CCK induced NF-κB nuclear translocation, and DNA binding was also blocked by GF-109203X and BAPTA. Direct activation of PKC with TPA induced mob-1 chemokine expression and activated NF-κB DNA binding to a similar extent as did CCK. Increasing intracellular Ca2+using ionomycin had no effect on mob-1 mRNA levels or NF-κB activity. Both CCK and TPA treatments decreased inhibitory κB-α (IκB-α) levels, whereas ionomycin had no effect. However, the effects of TPA on IκB-α degradation were less complete than for CCK. In combination, TPA and ionomycin degraded IκB-α to a similar extent as CCK. Therefore, activation of NF-κB and mob-1 expression by supraphysiological CCK is likely mediated by both PKC activation and elevated intracellular Ca2+.