Opposing effects of prostaglandin E2 receptors EP3 and EP4 on mouse and human ß-cell survival and proliferation.
Mol Metab
; 6(6): 548-559, 2017 06.
Article
em En
| MEDLINE
| ID: mdl-28580285
ABSTRACT
OBJECTIVE:
Hyperglycemia and systemic inflammation, hallmarks of Type 2 Diabetes (T2D), can induce the production of the inflammatory signaling molecule Prostaglandin E2 (PGE2) in islets. The effects of PGE2 are mediated by its four receptors, E-Prostanoid Receptors 1-4 (EP1-4). EP3 and EP4 play opposing roles in many cell types due to signaling through different G proteins, Gi and GS, respectively. We previously found that EP3 and EP4 expression are reciprocally regulated by activation of the FoxM1 transcription factor, which promotes ß-cell proliferation and survival. Our goal was to determine if EP3 and EP4 regulate ß-cell proliferation and survival and, if so, to elucidate the downstream signaling mechanisms.METHODS:
ß-cell proliferation was assessed in mouse and human islets ex vivo treated with selective agonists and antagonists for EP3 (sulprostone and DG-041, respectively) and EP4 (CAY10598 and L-161,982, respectively). ß-cell survival was measured in mouse and human islets treated with the EP3- and EP4-selective ligands in conjunction with a cytokine cocktail to induce cell death. Changes in gene expression and protein phosphorylation were analyzed in response to modulation of EP3 and EP4 activity in mouse islets.RESULTS:
Blockade of EP3 enhanced ß-cell proliferation in young, but not old, mouse islets in part through phospholipase C (PLC)-γ1 activity. Blocking EP3 also increased human ß-cell proliferation. EP4 modulation had no effect on ex vivo proliferation alone. However, blockade of EP3 in combination with activation of EP4 enhanced human, but not mouse, ß-cell proliferation. In both mouse and human islets, EP3 blockade or EP4 activation enhanced ß-cell survival in the presence of cytokines. EP4 acts in a protein kinase A (PKA)-dependent manner to increase mouse ß-cell survival. In addition, the positive effects of FoxM1 activation on ß-cell survival are inhibited by EP3 and dependent on EP4 signaling.CONCLUSIONS:
Our results identify EP3 and EP4 as novel regulators of ß-cell proliferation and survival in mouse and human islets ex vivo.Palavras-chave
COX-2, cyclooxygenase-2; Cell death; DAG, diacylglycerol; EP1-4, E-Prostanoid Receptors 1-4; GPCR, G protein-coupled receptor; IP3, inositol 1,4,5-trisphosphate; PGE2, prostaglandin E2; PKA, protein kinase A; PL, placental lactogen; PLC, phospholipase C; PT, pertussis toxin; Pancreatic ß-cell; Proliferation; Prostaglandin E2
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proliferação de Células
/
Células Secretoras de Insulina
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Receptores de Prostaglandina E Subtipo EP3
/
Receptores de Prostaglandina E Subtipo EP4
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Mol Metab
Ano de publicação:
2017
Tipo de documento:
Article
País de afiliação:
Estados Unidos