Inflammation and Experimental Surgery Unit, Centro de Investigación Biomédica en Red de Enfermedades Hepaticas y Digestivas, University Hospital Virgen de Arrixaca-Fundación Formación Investigación Sanitaria Región Murcia, Murcia, Spain.
FASEB J. 2012 Jul;26(7):2951-62. doi: 10.1096/fj.12-205765. Epub 2012 Apr 6.
Prostaglandins (PGs) are important lipid mediators involved in the development of inflammatory associated pain and fever. PGE2 is a well-established endogenous pyrogen activated by proinflammatory cytokine interleukin (IL)-1β. P2X7 receptors (P2X7Rs) expressed by inflammatory cells are stimulated by the danger signal extracellular ATP to activate the inflammasome and release IL-1β. Here we show that P2X7R activation is required for the release of PGE2 and other autacoids independent of inflammasome activation, with an ATP EC(50) for PGE2 and IL-1β release of 1.58 and 1.23 mM, respectively. Furthermore, lack of P2X7R or specific antagonism of P2X7R decreased the febrile response in mice triggered after intraperitoneal LPS or IL-1β inoculation. Accordingly, LPS inoculation caused intraperitoneal ATP accumulation. Therefore, P2X7R antagonists emerge as novel therapeutics for the treatment for acute inflammation, pain and fever, with wider anti-inflammatory activity than currently used cyclooxygenase inhibitors.-Barberà-Cremades, M., Baroja-Mazo, A., Gomez, A. I., Machado, F., Di Virgilio, F., Pelegrín, P. P2X7 receptor-stimulation causes fever via PGE2 and IL-1β release.
前列腺素（PGs）是参与炎症相关疼痛和发热发展的重要脂质介质。PGE2 是一种由促炎细胞因子白细胞介素（IL）-1β 激活的成熟内源性热原。炎症细胞表达的 P2X7 受体（P2X7Rs）被细胞外 ATP 的危险信号刺激，从而激活炎症小体并释放 IL-1β。在这里，我们表明 P2X7R 的激活是 PGE2 和其他自分泌物质释放所必需的，与炎症小体激活无关，PGE2 和 IL-1β 释放的 ATP EC（50）分别为 1.58 和 1.23 mM。此外，缺乏 P2X7R 或 P2X7R 的特异性拮抗作用可降低腹腔内 LPS 或 IL-1β接种后小鼠的发热反应。相应地，LPS 接种会导致腹腔内 ATP 积累。因此，P2X7R 拮抗剂作为治疗急性炎症、疼痛和发热的新型治疗药物出现，其抗炎活性比目前使用的环氧化酶抑制剂更广泛。-Barberà-Cremades, M., Baroja-Mazo, A., Gomez, A. I., Machado, F., Di Virgilio, F., Pelegrín, P. P2X7 受体刺激通过 PGE2 和 IL-1β 释放引起发热。
