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 Prem Singh, Meena Ananthanaravanan, George Perides, John A. Williams, Jeffery D. Molkentin, Sohail Z. Husain

Research output: Contribution to journalArticle

42 Citations (Scopus)

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

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Acinar Cells
Calcineurin
Bile Acids and Salts
Pancreatitis
Wounds and Injuries
Chemical activation
Pancreatic Ducts
Tacrolimus
Ducts
Bile Reflux
Chymotrypsinogen
NFATC Transcription Factors
Taurocholic Acid
Ethane
Propidium
Chelation
L-Lactate Dehydrogenase
Adenoviridae
Cyclosporine
Protein Isoforms

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Muili, K. A., Wang, D., Orabi, A. I., Sarwar, S., Luo, Y., Javed, T. A., ... 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

Bile acids induce pancreatic acinar cell injury and pancreatitis by activating calcineurin. / Muili, Kamaldeen A.; Wang, Dong; Orabi, Abrahim I.; Sarwar, Sheharyar; Luo, Yuhuan; Javed, Tanveer A.; Eisses, John F.; Mahmood, Syeda M.; Jin, Shunqian; Singh, Vijay Prem; Ananthanaravanan, Meena; Perides, George; Williams, John A.; Molkentin, Jeffery D.; Husain, Sohail Z.

In: Journal of Biological Chemistry, Vol. 288, No. 1, 04.01.2013, p. 570-580.

Research output: Contribution to journalArticle

Muili, KA, Wang, D, Orabi, AI, Sarwar, S, Luo, Y, Javed, TA, Eisses, JF, Mahmood, SM, Jin, S, Singh, VP, Ananthanaravanan, M, Perides, G, Williams, JA, Molkentin, JD & Husain, SZ 2013, 'Bile acids induce pancreatic acinar cell injury and pancreatitis by activating calcineurin', Journal of Biological Chemistry, vol. 288, no. 1, pp. 570-580. https://doi.org/10.1074/jbc.M112.428896
Muili, Kamaldeen A. ; Wang, Dong ; Orabi, Abrahim I. ; Sarwar, Sheharyar ; Luo, Yuhuan ; Javed, Tanveer A. ; Eisses, John F. ; Mahmood, Syeda M. ; Jin, Shunqian ; Singh, Vijay Prem ; Ananthanaravanan, Meena ; Perides, George ; Williams, John A. ; Molkentin, Jeffery D. ; Husain, Sohail Z. / Bile acids induce pancreatic acinar cell injury and pancreatitis by activating calcineurin. In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 1. pp. 570-580.
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AU - Luo, Yuhuan

AU - Javed, Tanveer A.

AU - Eisses, John F.

AU - Mahmood, Syeda M.

AU - Jin, Shunqian

AU - Singh, Vijay Prem

AU - Ananthanaravanan, Meena

AU - Perides, George

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N2 - 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.

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