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

Awla, Darbaz LU ; Zetterqvist, Anna LU ; Abdulla, Aree LU ; Camello, Cristina; Berglund, Lisa LU ; Spégel, Peter LU ; Pozo, Maria J; Camello, Pedro J; Regnér, Sara LU and Gomez, Maria LU , et al. (2012) In Gastroenterology 143(5). p.1352-1352
Abstract
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... (More)
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. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Gastroenterology
volume
143
issue
5
pages
1352 - 1352
publisher
W B Saunders
external identifiers
  • wos:000310459700048
  • pmid:22841788
  • scopus:84868018808
ISSN
1528-0012
DOI
10.1053/j.gastro.2012.07.098
language
English
LU publication?
yes
id
158b767d-2f26-4551-8edf-c6baa3ba0bd1 (old id 2966441)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/22841788?dopt=Abstract
date added to LUP
2012-08-10 09:17:28
date last changed
2017-10-08 04:29:10
@article{158b767d-2f26-4551-8edf-c6baa3ba0bd1,
  abstract     = {BACKGROUND &amp; AIMS: <br/><br>
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. <br/><br>
<br/><br>
METHODS: <br/><br>
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. <br/><br>
<br/><br>
RESULTS: <br/><br>
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. <br/><br>
<br/><br>
CONCLUSIONS: <br/><br>
NFATc3 regulates trypsinogen activation, inflammation, and pancreatic tissue damage during development of AP in mice, and might be a therapeutic target.},
  author       = {Awla, Darbaz and Zetterqvist, Anna and Abdulla, Aree and Camello, Cristina and Berglund, Lisa and Spégel, Peter and Pozo, Maria J and Camello, Pedro J and Regnér, Sara and Gomez, Maria and Thorlacius, Henrik},
  issn         = {1528-0012},
  language     = {eng},
  number       = {5},
  pages        = {1352--1352},
  publisher    = {W B Saunders},
  series       = {Gastroenterology},
  title        = {NFATc3 Regulates Trypsinogen Activation, Neutrophil Recruitment, and Tissue Damage in Acute Pancreatitis in Mice.},
  url          = {http://dx.doi.org/10.1053/j.gastro.2012.07.098},
  volume       = {143},
  year         = {2012},
}