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NFATc3 Regulates Trypsinogen Activation, Neutrophil Recruitment, and Tissue Damage in Acute Pancreatitis in Mice.

  • Darbaz Awla
  • Anna Zetterqvist
  • Aree Abdulla
  • Cristina Camello
  • Lisa Berglund
  • Peter Spégel
  • Maria J Pozo
  • Pedro J Camello
  • Sara Regnér
  • Maria Gomez
  • Henrik Thorlacius
Publishing year: 2012
Language: English
Pages: 1352-1352
Publication/Series: Gastroenterology
Volume: 143
Issue: 5
Document type: Journal article
Publisher: W B Saunders

Abstract english


The signaling mechanisms that regulate trypsinogen activation and inflammation in acute pancreatitis (AP) are unclear. We explored the involvement of the calcium- and calcineurin-dependent transcription factor nuclear factor of activated T-cells (NFAT) in development of AP in mice.


We measured levels of myeloperoxidase and macrophage inflammatory protein-2 (CXCL2), trypsinogen activation, and tissue damage in the pancreas 24 h after induction of AP by retrograde infusion of taurocholate into the pancreatic ducts of wild-type, NFAT luciferase reporter (NFAT-luc), and NFATc3-deficient mice. We isolated acinar cells and measured NFAT nuclear accumulation, trypsin activity, and expression of NFAT-regulated genes.


Infusion of taurocholate increased the transcriptional activity of NFAT in the pancreas, aorta, lung, and spleen of NFAT-luc mice. Inhibition of NFAT with A-285222 blocked taurocholate-induced activation of NFAT in all organs. A-285222 also reduced taurocholate-induced increases in levels of amylase, myeloperoxidase and CXCL2; activation of trypsinogen; necrosis of acinar cells; edema; leukocyte infiltration; and hemorrhage in the pancreas. NFATc3-deficient mice were protected from these effects of taurocholate. Similar results were obtained using an L-arginine-induced model of AP. Reverse transcriptase PCR and confocal immunofluorescence analyses showed that NFATc3 is expressed by acinar cells. NFATc3 expression was activated by stimuli that increase intracellular calcium; activation was prevented by the calcineurin blocker cyclosporine A or A-285222. Activation of trypsinogen by secretagogues in acinar cells was prevented by pharmacologic inhibition of NFAT signaling or lack of NFATc3. A-285222 also reduced expression of inflammatory cytokines such as CXCL2 in acinar cells.


NFATc3 regulates trypsinogen activation, inflammation, and pancreatic tissue damage during development of AP in mice, and might be a therapeutic target.


  • Gastroenterology and Hepatology


  • Surgery Research
  • Molecular Metabolism
  • ISSN: 1528-0012
Peter Spegel
E-mail: peter [dot] spegel [at] chem [dot] lu [dot] se


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