A Functional Analysis of EP4 Receptor‐Expressing Neurons in Mediating the Action of Prostaglandin E2 Within Specific Nuclei of the Brain in Response to Circulating Interleukin‐1β
A Functional Analysis of EP4 Receptor‐Expressing Neurons in Mediating the Action of Prostaglandin E2 Within Specific Nuclei of the Brain in Response to Circulating Interleukin‐1β
复制标题
EP4 受体表达神经元介导特定脑核内前列腺素 E2 响应循环白细胞介素 1β 的作用的功能分析
作者：
Ji Zhang;S. Rivest
摘要：髓系细胞释放的促炎细胞因子能够通过血脑屏障细胞释放的中间分子刺激不同的神经元群。本研究的目的是验证以下假设：前列腺素 (PG) 通过 E2 型 PG 与其 EP4 受体之间的特殊相互作用，在激活选择性神经元组中发挥位点特异性作用。在第一组实验中，用 PG 合成抑制剂酮咯酸治疗动物，以确定 PG 在介导响应循环白细胞介素-1β (IL-1β) 的神经元激活和 EP4 表达中的内源性贡献。随后的实验包括评估 PGE2 在激活大鼠大脑中表达 EP4 的神经元中的作用。酮咯酸完全消除了肝脏中 PGE2 的内源性释放，并阻止了特定神经元群（例如小细胞室旁核和 A1 儿茶酚胺能细胞群）中立即早期基因的诱导和 EP4 mRNA 的上调。然而，这种效应并未遍及整个大脑，因为 PGE2 抑制未能消除孤束核、臂旁核、终纹床核和室周器官中 IL-1β 诱导的 c-fos 转录。令人感兴趣的数据是，当动物接受酮咯酸预处理时，中央 PGE2 注射激活了神经元中的 EP4 基因转录，而这些神经元不再对静脉注射 IL-1β 推注有反应。脑室内 PGE2 输注响应于表达 EP4 的神经元内诱导 c-fos 免疫反应性核，进一步支持了配体与其受体之间的位点特异性相互作用。脑室内 PGE2 和静脉注射 IL-1β 都会引起血浆皮质酮水平急剧上升，而在 IL-1β 攻击的大鼠中，抑制 PG 产生的效果完全被阻止。这些数据提供了证据，表明 EP4 在参与自主神经和神经内分泌控制的许多细胞核中表达，尽管特殊的相互作用似乎发生在特定的细胞核和区域，包括内分泌下丘脑和腹外侧延髓的 A1 细胞群。 EP4很可能作为PGE2的功能受体来激活参与糖皮质激素轴激活的神经元回路，作为适当控制全身炎症的重要神经内分泌反应。
Abstract: Proinflammatory cytokines released by cells of myeloid lineage have the ability to stimulate different populations of neurons through intermediate molecules released by cells of the blood‐brain barrier. The aim of the present study was to verify the hypothesis that prostaglandins (PGs) play a site‐specific role in activating selective groups of neurons via a privileged interaction between PG of the E2 type and its EP4 receptor. In a first set of experiments, animals were treated with the inhibitor of PG synthesis ketorolac to determine the endogenous contribution of PG in mediating the neuronal activation and EP4 expression in response to circulating interleukin‐1β (IL‐1β). The subsequent experiment consisted of evaluating the role of PGE2 in activating EP4‐expressing neurons in the rat brain. Ketorolac completely abolished the endogenous release of PGE2 in the liver and prevented the induction of immediate‐early genes and up‐regulation of EP4 mRNA in specific groups of neurons, such as the parvocellular paraventricular nucleus and the A1 catecholaminergic population of cells. This effect was, however, not generalized throughout the brain as PGE2 inhibition failed to abolish IL‐1β‐induced c‐fos transcription in the nucleus of the solitary tract, parabrachial nucleus, bed nucleus of the stria terminalis, and the circumventricular organs. Of interest are the data that central PGE2 injection activated EP4 gene transcription in neurons that no longer responded to the intravenous IL‐1β bolus when the animals were pretreated with ketorolac. Site‐specific interaction between the ligand and its receptor was further supported by the induction of c‐fos‐immunoreactive nuclei within EP4‐expressing neurons in response to intracerebroventricular PGE2 infusion. Both intracerebroventricular PGE2 and intravenous IL‐1β injection provoked a sharp and rapid increase in plasma corticosterone levels, an effect that was completely prevented in inhibiting PG production in IL‐1β‐challenged rats. These data provide the evidence that EP4 is expressed in numerous nuclei involved in autonomic and neuroendocrine control, although a privileged interaction seems to take place in specific nuclei and areas, including the endocrine hypothalamus and the A1 cell group of the ventrolateral medulla. It is quite possible that EP4 acts as the functional receptor for PGE2 to activate the neuronal circuit involved in the activation of the glucocorticoid axis, as an essential neuroendocrine response for the appropriate control of systemic inflammation.
影响因子：
56.9
作者：
SAPOLSKY, R;RIVIER, C;VALE, W
通讯作者：
VALE, W
IL-1 对大鼠促肾上腺皮质激素分泌的刺激作用：它是否受前列腺素调节？
影响因子：
4.8
作者：
Rivier,C;Vale,W
通讯作者：
Vale,W