Elsevier

Molecular Metabolism

Volume 6, Issue 6, June 2017, Pages 548-559
Molecular Metabolism

Original Article
Opposing effects of prostaglandin E2 receptors EP3 and EP4 on mouse and human β-cell survival and proliferation

https://doi.org/10.1016/j.molmet.2017.04.002Get rights and content
Under a Creative Commons license
open access

Highlights

  • EP3 inhibits mouse and human β-cell proliferation and increases β-cell death.

  • Inhibition of EP3 acts in part via PLC-γ1 to increase mouse β-cell proliferation.

  • EP4 enhances human but not mouse β-cell proliferation in the presence of EP3 inhibition and promotes β-cell survival in mouse and human islets.

  • EP4 acts through a PKA-dependent mechanism to protect against mouse β-cell death.

  • Pro-survival effects of FoxM1 activation are inhibited by EP3 and dependent on EP4.

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 β-cell proliferation and survival. Our goal was to determine if EP3 and EP4 regulate β-cell proliferation and survival and, if so, to elucidate the downstream signaling mechanisms.

Methods

β-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). β-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 β-cell proliferation in young, but not old, mouse islets in part through phospholipase C (PLC)-γ1 activity. Blocking EP3 also increased human β-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, β-cell proliferation. In both mouse and human islets, EP3 blockade or EP4 activation enhanced β-cell survival in the presence of cytokines. EP4 acts in a protein kinase A (PKA)-dependent manner to increase mouse β-cell survival. In addition, the positive effects of FoxM1 activation on β-cell survival are inhibited by EP3 and dependent on EP4 signaling.

Conclusions

Our results identify EP3 and EP4 as novel regulators of β-cell proliferation and survival in mouse and human islets ex vivo.

Author Video

Download : Download video (14MB)

Author Video. Watch what authors say about their articles

Keywords

Pancreatic β-cell
Prostaglandin E2
Proliferation
Cell death

Abbreviations

GPCR
G protein-coupled receptor
PGE2
prostaglandin E2
EP1-4
E-Prostanoid Receptors 1-4
PLC
phospholipase C
IP3
inositol 1,4,5-trisphosphate
DAG
diacylglycerol
PL
placental lactogen
PT
pertussis toxin
PKA
protein kinase A
COX-2
cyclooxygenase-2

Cited by (0)