Bile acids induce pancreatic acinar cell injury and pancreatitis by activating calcineurin

Kamaldeen A. Muili, Dong Wang, Abrahim I. Orabi, Sheharyar Sarwar, Yuhuan Luo, Tanveer A. Javed, John F. Eisses, Syeda M. Mahmood, Shunqian Jin, Vijay P. Singh, Meena Ananthanaravanan, George Perides, John A. Williams, Jeffery D. Molkentin, Sohail Z. Husain

Research output: Contribution to journalArticle

46 Scopus citations

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 Ca2+. Thus, it would be clinically relevant to know the targets of this aberrant Ca2+ signal. We hypothesized that the Ca2+-activated phosphatase calcineurin is such a Ca2+ 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 Ca2+. 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-κ Bactivation. 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 Ca2+ generated by bile acid exposure, bile acid-induced pancreatic injury is dependent on calcineurin activation, and calcineurin inhibitorsmayprovide an adjunctive therapy for biliary pancreatitis.

Original languageEnglish (US)
Pages (from-to)570-580
Number of pages11
JournalJournal of Biological Chemistry
Volume288
Issue number1
DOIs
StatePublished - Jan 4 2013

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Bile acids induce pancreatic acinar cell injury and pancreatitis by activating calcineurin'. Together they form a unique fingerprint.

  • Cite this

    Muili, K. A., Wang, D., Orabi, A. I., Sarwar, S., Luo, Y., Javed, T. A., Eisses, J. F., Mahmood, S. M., Jin, S., Singh, V. P., Ananthanaravanan, M., Perides, G., Williams, J. A., Molkentin, J. D., & Husain, S. Z. (2013). Bile acids induce pancreatic acinar cell injury and pancreatitis by activating calcineurin. Journal of Biological Chemistry, 288(1), 570-580. https://doi.org/10.1074/jbc.M112.428896