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Maria Gomez

Maria Gomez

Professor

Maria Gomez

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

Author

  • Darbaz Awla
  • Anna Zetterqvist
  • Aree Abdulla
  • Cristina Camello
  • Lisa Berglund
  • Peter Spégel
  • Maria J Pozo
  • Pedro J Camello
  • Sara Regnér
  • Maria Gomez
  • Henrik Thorlacius

Summary, in English

BACKGROUND & AIMS:

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.



METHODS:

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.



RESULTS:

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.



CONCLUSIONS:

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

Department/s

  • Surgery
  • Department of Clinical Sciences, Malmö
  • Diabetes - Molecular Metabolism
  • EXODIAB: Excellence in Diabetes Research in Sweden

Publishing year

2012

Language

English

Pages

1352-1352

Publication/Series

Gastroenterology

Volume

143

Issue

5

Document type

Journal article

Publisher

Elsevier

Topic

  • Gastroenterology and Hepatology

Status

Published

Research group

  • Surgery
  • Diabetes - Molecular Metabolism

ISBN/ISSN/Other

  • ISSN: 1528-0012