title: Pancreatic acinar cell nuclear factor κB activation because of bile acid exposure is dependent on calcineurin.
abstract: Biliary pancreatitis is the most common etiology of acute pancreatitis, accounting for 30-60% of cases. A dominant theory for the development of biliary pancreatitis is the reflux of bile into the pancreatic duct and subsequent exposure to pancreatic acinar cells. Bile acids are known to induce aberrant Ca(2+) signals in acinar cells as well as nuclear translocation of NF-κB. In this study, we examined the role of the downstream Ca(2+) target calcineurin on NF-κB translocation. Freshly isolated mouse acinar cells were infected for 24 h with an adenovirus expressing an NF-κB luciferase reporter. The bile acid taurolithocholic acid-3-sulfate caused NF-κB activation at concentrations (500 μm) that were associated with cell injury. We show that the NF-κB inhibitor Bay 11-7082 (1 μm) blocked translocation and injury. Pretreatment with the Ca(2+) chelator 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, the calcineurin inhibitors FK506 and cyclosporine A, or use of acinar cells from calcineurin Aβ-deficient mice each led to reduced NF-κB activation with taurolithocholic acid-3-sulfate. Importantly, these manipulations did not affect LPS-induced NF-κB activation. A critical upstream regulator of NF-κB activation is protein kinase C, which translocates to the membranes of various organelles in the active state. We demonstrate that pharmacologic and genetic inhibition of calcineurin blocks translocation of the PKC-δ isoform. In summary, bile-induced NF-κB activation and acinar cell injury are mediated by calcineurin, and a mechanism for this important early inflammatory response appears to be upstream at the level of PKC translocation.
authors.affiliation: From the Department of Pediatrics and.
authors.forename: Kamaldeen A
authors.initials: KA
authors.lastname: Muili
authors.affiliation: From the Department of Pediatrics and.
authors.forename: Shunqian
authors.initials: S
authors.lastname: Jin
authors.affiliation: From the Department of Pediatrics and.
authors.forename: Abrahim I
authors.initials: AI
authors.lastname: Orabi
authors.affiliation: From the Department of Pediatrics and.
authors.forename: John F
authors.initials: JF
authors.lastname: Eisses
authors.affiliation: From the Department of Pediatrics and.
authors.forename: Tanveer A
authors.initials: TA
authors.lastname: Javed
authors.affiliation: From the Department of Pediatrics and.
authors.forename: Tianming
authors.initials: T
authors.lastname: Le
authors.affiliation: Internal Medicine, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center and the University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
authors.forename: Rita
authors.initials: R
authors.lastname: Bottino
authors.affiliation: Internal Medicine, Children's Hospital of Pittsburgh of the University of Pittsburgh Medical Center and the University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224.
authors.forename: Thotalla
authors.initials: T
authors.lastname: Jayaraman
authors.affiliation: From the Department of Pediatrics and. Electronic address: sohail.husain@chp.edu.
authors.forename: Sohail Z
authors.initials: SZ
authors.lastname: Husain
mesh_terms: D061354:Acinar Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001647:Bile Acids and Salts / Q000494:pharmacology*; D019703:Calcineurin / Q000378:metabolism*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism*; D010179:Pancreas / Q000473:pathology*; D051745:Protein Kinase C-delta / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D013658:Taurolithocholic Acid / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D001647:Bile Acids and Salts; D008070:Lipopolysaccharides; D016328:NF-kappa B; C066776:taurolithocholic acid 3-sulfate; D013658:Taurolithocholic Acid; D051745:Protein Kinase C-delta; D019703:Calcineurin
keywords: Acinar Cell; Bile acid; Calcineurin; Calcium Signaling; NF-κB; PKC; Pancreas; Pancreatitis