title: Bile acids induce pancreatic acinar cell injury and pancreatitis by activating calcineurin.
abstract: Biliary pancreatitis is the leading cause of acute pancreatitis in both children and adults. A proposed mechanism is the reflux of bile into the pancreatic duct. Bile acid exposure causes pancreatic acinar cell injury through a sustained rise in cytosolic Ca(2+). Thus, it would be clinically relevant to know the targets of this aberrant Ca(2+) signal. We hypothesized that the Ca(2+)-activated phosphatase calcineurin is such a Ca(2+) target. To examine calcineurin activation, we infected primary acinar cells from mice with an adenovirus expressing the promoter for a downstream calcineurin effector, nuclear factor of activated T-cells (NFAT). The bile acid taurolithocholic acid-3-sulfate (TLCS) was primarily used to examine bile acid responses. TLCS caused calcineurin activation only at concentrations that cause acinar cell injury. The activation of calcineurin by TLCS was abolished by chelating intracellular Ca(2+). Pretreatment with 1,2-bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (acetoxymethyl ester) (BAPTA-AM) or the three specific calcineurin inhibitors FK506, cyclosporine A, or calcineurin inhibitory peptide prevented bile acid-induced acinar cell injury as measured by lactate dehydrogenase leakage and propidium iodide uptake. The calcineurin inhibitors reduced the intra-acinar activation of chymotrypsinogen within 30 min of TLCS administration, and they also prevented NF-κB activation. In vivo, mice that received FK506 or were deficient in the calcineurin isoform Aβ (CnAβ) subunit had reduced pancreatitis severity after infusion of TLCS or taurocholic acid into the pancreatic duct. In summary, we demonstrate that acinar cell calcineurin is activated in response to Ca(2+) generated by bile acid exposure, bile acid-induced pancreatic injury is dependent on calcineurin activation, and calcineurin inhibitors may provide an adjunctive therapy for biliary pancreatitis.
authors.affiliation: Department of Pediatrics, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center and the University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15224, USA.
authors.forename: Kamaldeen A
authors.initials: KA
authors.lastname: Muili
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.forename: Abrahim I
authors.initials: AI
authors.lastname: Orabi
authors.forename: Sheharyar
authors.initials: S
authors.lastname: Sarwar
authors.forename: Yuhuan
authors.initials: Y
authors.lastname: Luo
authors.forename: Tanveer A
authors.initials: TA
authors.lastname: Javed
authors.forename: John F
authors.initials: JF
authors.lastname: Eisses
authors.forename: Syeda M
authors.initials: SM
authors.lastname: Mahmood
authors.forename: Shunqian
authors.initials: S
authors.lastname: Jin
authors.forename: Vijay P
authors.initials: VP
authors.lastname: Singh
authors.forename: Meena
authors.initials: M
authors.lastname: Ananthanaravanan
authors.forename: George
authors.initials: G
authors.lastname: Perides
authors.forename: John A
authors.initials: JA
authors.lastname: Williams
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.forename: Sohail Z
authors.initials: SZ
authors.lastname: Husain
mesh_terms: D061354:Acinar Cells / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000737:chemistry*; D019703:Calcineurin / Q000378:metabolism*; D002118:Calcium / Q000737:chemistry* / Q000378:metabolism; D002918:Chymotrypsin / Q000737:chemistry; D003600:Cytosol / Q000378:metabolism*; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000737:chemistry; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism*; D010195:Pancreatitis / Q000378:metabolism*; D020033:Protein Isoforms; D016559:Tacrolimus / Q000494:pharmacology; D013658:Taurolithocholic Acid / Q000031:analogs & derivatives / Q000737:chemistry; D013997:Time Factors
chemical_list: D001647:Bile Acids and Salts; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D020033:Protein Isoforms; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; C066776:taurolithocholic acid 3-sulfate; D013658:Taurolithocholic Acid; D004533:Egtazic Acid; D007770:L-Lactate Dehydrogenase; D019703:Calcineurin; D002918:Chymotrypsin; D002118:Calcium; D016559:Tacrolimus