Nuclear Factor-κB Increases Intracellular Calcium by Upregulation of Na(+)-Ca(2+) Exchanger 1 in Cerulein-Induced Acute Pancreatitis

OBJECTIVES: The mechanisms underlying pathogenesis of acute pancreatitis (AP) are still not completely understood. An early, critical feature of AP is aberrant calcium (Ca(2+)) signaling, termed Ca(2+) overload, within pancreatic acinar cells. This study aimed to develop a model system in rats for AP induction to study the contribution of the Na(+)-Ca(2+) exchanger 1 (NCX1) ion channel in AP pathogenesis. METHODS: To establish a rat model of AP induction, cerulein or l-arginine were intraperitoneally injected and tissue was histologically analyzed by hematoxylin and eosin staining. A cell culture-based model for AP induction was similarly created through cerulein treatment of AR42J cells. Induction of AP was also examined following exposure to the NXC1-targeted inhibitor KB-R7943. The expression of each gene was detected by Western blotting, immunofluorescence, immunohistochemistry, or quantitative reverse transcription polymerase chain reaction. Transcriptional regulation by nuclear factor (NF)-κB was detected using an NCX1 promoter-fusion dual luciferase reporter system. Cytosolic Ca(2+) was measured using a fluorescent calcium indicator. RESULTS: We found that cerulein induced NCX1 expression via activation of nuclear factor NF-κB, which potentially binds to the NCX1 promoter to induce its transcription. CONCLUSIONS: Our findings reveal a regulatory pathway through NF-κB/NCX1 governing Ca(2+) overload in AP development, thus providing potential targets for AP treatment.