Phosphatidylinositide 3-kinase gamma regulates key pathologic responses to cholecystokinin in pancreatic acinar cells.
Gastroenterology
; 126(2): 554-66, 2004 Feb.
Article
em En
| MEDLINE
| ID: mdl-14762792
ABSTRACT
BACKGROUND & AIMS:
Early events in the pancreatic acinar cell critical for development of pancreatitis include activation of the transcription factor nuclear factor kappa B (NF-kappa B), abnormal Ca(2+) responses, and trypsinogen activation. Mechanisms underlying these responses, which can be studied in isolated pancreatic acini stimulated with supraphysiologic doses of cholecystokinin (CCK-8), remain poorly understood. We here report that these responses are regulated by phosphatidylinositide 3-kinase (PI3K) gamma.METHODS:
To inactivate PI3K, we used mice deficient in the catalytic PI3K gamma subunit p110 gamma as well as the PI3K inhibitors LY294002 and wortmannin. We measured Ca(2+) responses by using Fura-2, NF-kappa B-binding activity by electromobility shift assay, I kappa B degradation by Western blotting, and trypsinogen activation by fluorogenic assay.RESULTS:
CCK-induced intracellular Ca(2+) mobilization, Ca(2+) influx, trypsinogen, and NF-kappa B activation were all diminished in pancreatic acini isolated from p110 gamma(-/-) mice. Both in mouse and rat acini, these responses were inhibited by the PI3K inhibitors. The Ca(2+) signal and trypsinogen activation were similarly reduced in acini isolated from p110 gamma(-/-) and p110 gamma(+/-) mice compared with wild-type mice. By contrast, NF-kappa B activation was inhibited in p110 gamma(-/-) acini but not in p110 gamma(+/-) acini. These differences indicate that the mechanism of NF-kappa B regulation by PI3K gamma differs from those for the Ca(2+) and trypsinogen responses. CCK-induced responses in p110 gamma(-/-) acini were all further inhibited by LY294002, indicating the involvement of other PI3K isoform(s), in addition to PI3K gamma.CONCLUSIONS:
The results show that key pathologic responses of the pancreatic acinar cell are regulated by PI3K gamma and suggest an important role for this PI3K isoform in pancreatitis.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pâncreas
/
Sincalida
/
Fosfatidilinositol 3-Quinases
Limite:
Animals
Idioma:
En
Ano de publicação:
2004
Tipo de documento:
Article