NFATc3 Regulates Trypsinogen Activation, Neutrophil Recruitment, and Tissue Damage in Acute Pancreatitis in Mice.
(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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https://lup.lub.lu.se/record/2966441
- author
- organization
- publishing date
- 2012
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Gastroenterology
- volume
- 143
- issue
- 5
- pages
- 1352 - 1352
- publisher
- Elsevier
- external identifiers
-
- wos:000310459700048
- pmid:22841788
- scopus:84868018808
- pmid:22841788
- ISSN
- 1528-0012
- DOI
- 10.1053/j.gastro.2012.07.098
- language
- English
- LU publication?
- yes
- additional info
- The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Surgery Research Unit (013242220), Molecular Metabolism (013244000), Emergency medicine/Medicine/Surgery (013240200)
- 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
- 2016-04-04 07:53:53
- date last changed
- 2022-01-29 02:43:40
@article{158b767d-2f26-4551-8edf-c6baa3ba0bd1, abstract = {{BACKGROUND & 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 = {{Elsevier}}, 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}}, doi = {{10.1053/j.gastro.2012.07.098}}, volume = {{143}}, year = {{2012}}, }