P2X7 receptor-stimulation causes fever via PGE2 and IL-1β release

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)-1 beta. P2X7 receptors (P2X7Rs) expressed by inflammatory cells are stimulated by the danger signal extracellular ATP to activate the inflammasome and release IL-1 beta. Here we show that P2X7R activation is required for the release of PGE2 and other autacoids independent of inflammasome activation, with an ATP EC50 for PGE2 and IL-1 beta 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-1 beta 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.-Barbera-Cremades, M., Baroja-Mazo, A., Gomez, A. I., Machado, F., Di Virgilio, F., Pelegrin, P. P2X7 receptor-stimulation causes fever via PGE2 and IL-1 beta release. FASEB J. 26, 2951-2962 (2012). www.fasebj.org