前列腺素 E 受体 EP3 和 EP4 对小鼠和人β细胞存活和增殖的相反作用。
Opposing effects of prostaglandin E receptors EP3 and EP4 on mouse and human β-cell survival and proliferation.
机构信息
Department of Veterans Affairs, Tennessee Valley Health Authority, Nashville, TN, USA.
Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
出版信息
Mol Metab. 2017 Apr 5;6(6):548-559. doi: 10.1016/j.molmet.2017.04.002. eCollection 2017 Jun.
OBJECTIVE
Hyperglycemia and systemic inflammation, hallmarks of Type 2 Diabetes (T2D), can induce the production of the inflammatory signaling molecule Prostaglandin E (PGE) in islets. The effects of PGE 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, G and G, 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 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 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 .
目的
2 型糖尿病（T2D）的标志是高血糖和全身炎症，这会导致胰岛中炎症信号分子前列腺素 E（PGE）的产生。PGE 的作用是通过其四个受体，即前列腺素 E 受体 1-4（EP1-4）来介导的。由于通过不同的 G 蛋白，即 G 和 G 进行信号转导，EP3 和 EP4 在许多细胞类型中发挥相反的作用。我们之前发现，FoxM1 转录因子的激活会反向调节 EP3 和 EP4 的表达，FoxM1 促进β细胞的增殖和存活。我们的目标是确定 EP3 和 EP4 是否调节β细胞的增殖和存活，如果是，阐明下游信号转导机制。
方法
用选择性激动剂和拮抗剂处理小鼠和人胰岛，评估 EP3（sulprostone 和 DG-041，分别）和 EP4（CAY10598 和 L-161982，分别）对β细胞增殖的影响。用 EP3 和 EP4 选择性配体与细胞因子鸡尾酒处理小鼠和人胰岛，测量β细胞的存活情况。分析在调节 EP3 和 EP4 活性后，在小鼠胰岛中基因表达和蛋白磷酸化的变化。
结果
阻断 EP3 可增强年轻而非老年小鼠胰岛中的β细胞增殖，部分原因是通过磷脂酶 C（PLC）-γ1 活性。阻断 EP3 也增加了人类β细胞的增殖。单独调节 EP4 对增殖没有影响。然而，阻断 EP3 与激活 EP4 联合增强了人类而不是小鼠的β细胞增殖。在小鼠和人胰岛中，阻断 EP3 或激活 EP4 在存在细胞因子的情况下增强β细胞的存活。EP4 通过蛋白激酶 A（PKA）依赖性方式增加小鼠β细胞的存活。此外，FoxM1 激活对β细胞存活的积极影响被 EP3 抑制，并且依赖于 EP4 信号。
结论
我们的研究结果表明，EP3 和 EP4 是调节小鼠和人胰岛中β细胞增殖和存活的新型调节剂。
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