title: NFATc3 regulates trypsinogen activation, neutrophil recruitment, and tissue damage in acute pancreatitis in mice.
abstract: OBJECTIVE
  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 hours 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-transcription polymerase chain reaction and confocal immunofluorescence analyses showed that NFATc3 is expressed by acinar cells. NFATc3 expression was activated by stimuli that increase intracellular calcium levels, and activation was prevented by the calcineurin blocker cyclosporin 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.
authors: Department of Clinical Sciences, Section of Surgery, Skåne University Hospital, Malmö, Sweden.
authors: Darbaz
authors: D
authors: Awla
authors: Department of Clinical Sciences, Vascular Excitation-Transcription Coupling, Lund University, Malmö, Sweden.
authors: Anna V
authors: AV
authors: Zetterqvist
authors: Department of Clinical Sciences, Section of Surgery, Skåne University Hospital, Malmö, Sweden.
authors: Aree
authors: A
authors: Abdulla
authors: Department of Physiology, Nursing School, University of Extremadura, Caceres, Spain.
authors: Cristina
authors: C
authors: Camello
authors: Department of Clinical Sciences, Vascular Excitation-Transcription Coupling, Lund University, Malmö, Sweden.
authors: Lisa M
authors: LM
authors: Berglund
authors: Department of Clinical Sciences, Molecular Metabolism, Lund University, Malmö, Sweden.
authors: Peter
authors: P
authors: Spégel
authors: Department of Physiology, Nursing School, University of Extremadura, Caceres, Spain.
authors: Maria J
authors: MJ
authors: Pozo
authors: Department of Physiology, Nursing School, University of Extremadura, Caceres, Spain.
authors: Pedro J
authors: PJ
authors: Camello
authors: Department of Clinical Sciences, Section of Surgery, Skåne University Hospital, Malmö, Sweden.
authors: Sara
authors: S
authors: Regnér
authors: Department of Clinical Sciences, Vascular Excitation-Transcription Coupling, Lund University, Malmö, Sweden.
authors: Maria F
authors: MF
authors: Gomez
authors: Department of Clinical Sciences, Section of Surgery, Skåne University Hospital, Malmö, Sweden. Electronic address: henrik.thorlacius@med.lu.se.
authors: Henrik
authors: H
authors: Thorlacius
mesh_terms: D061354:Acinar Cells / Q000187:drug effects / Q000378:metabolism*; D000681:Amylases / Q000097:blood / Q000187:drug effects; D000818:Animals; D001011:Aorta / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D054426:Chemokine CXCL2 / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D051379:Mice; D050778:NFATC Transcription Factors / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D010195:Pancreatitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009195:Peroxidase / Q000187:drug effects / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D015398:Signal Transduction; D013154:Spleen / Q000378:metabolism; D018709:Statistics, Nonparametric; D013656:Taurocholic Acid; D014362:Trypsinogen / Q000187:drug effects / Q000378:metabolism*
chemical_list: C494244:A 285222; D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D050778:NFATC Transcription Factors; C494009:Nfatc3 protein, mouse; D011720:Pyrazoles; D013656:Taurocholic Acid; D014362:Trypsinogen; D009195:Peroxidase; D000681:Amylases