CCK stimulates mob-1 expression and NF-kappaB activation via protein kinase C and intracellular Ca(2+).
Supraphysiological concentrations of cholecystokinin (CCK) induce chemokine expression in rat pancreatic acini through the activation of the transcription factor NF-kappaB. 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 Ca(2+) chelator BAPTA. CCK induced NF-kappaB 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-kappaB DNA binding to a similar extent as did CCK. Increasing intracellular Ca(2+) using ionomycin had no effect on mob-1 mRNA levels or NF-kappaB activity. Both CCK and TPA treatments decreased inhibitory kappaB-alpha (IkappaB-alpha) levels, whereas ionomycin had no effect. However, the effects of TPA on IkappaB-alpha degradation were less complete than for CCK. In combination, TPA and ionomycin degraded IkappaB-alpha to a similar extent as CCK. Therefore, activation of NF-kappaB and mob-1 expression by supraphysiological CCK is likely mediated by both PKC activation and elevated intracellular Ca(2+).
Han
B
B
Department of Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0622, USA.
Logsdon
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D000818:Animals; D001692:Biological Transport / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism*; D002273:Carcinogens / Q000494:pharmacology; D002467:Cell Nucleus / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D002766:Cholecystokinin / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000502:physiology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D015759:Ionomycin / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D010179:Pancreas / Q000166:cytology / Q000201:enzymology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D002273:Carcinogens; D002614:Chelating Agents; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; C091326:Cxcl10 protein, rat; D016207:Cytokines; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007211:Indoles; D007476:Ionophores; D008301:Maleimides; D016328:NF-kappa B; D012333:RNA, Messenger; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; D015759:Ionomycin; D002766:Cholecystokinin; D011493:Protein Kinase C; C070515:bisindolylmaleimide I; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium