title: P2X7 receptor-stimulation causes fever via PGE2 and IL-1β release.
abstract: 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.
authors.affiliation: 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.
authors.forename: Maria
authors.initials: M
authors.lastname: Barberà-Cremades
authors.forename: Alberto
authors.initials: A
authors.lastname: Baroja-Mazo
authors.forename: Ana I
authors.initials: AI
authors.lastname: Gomez
authors.forename: Francisco
authors.initials: F
authors.lastname: Machado
authors.forename: Francesco
authors.initials: F
authors.lastname: Di Virgilio
authors.forename: Pablo
authors.initials: P
authors.lastname: Pelegrín
mesh_terms: D000255:Adenosine Triphosphate / Q000008:administration & dosage / Q000378:metabolism; D000818:Animals; D020013:Calcium Signaling; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000502:physiology*; D005334:Fever / Q000209:etiology* / Q000503:physiopathology*; D006801:Humans; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000502:physiology; D007274:Injections, Intraperitoneal; D053583:Interleukin-1beta / Q000008:administration & dosage / Q000502:physiology*; D007975:Leukotriene B4 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000008:administration & dosage; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058911:Purinergic P2X Receptor Agonists / Q000494:pharmacology; D058920:Purinergic P2X Receptor Antagonists / Q000494:pharmacology; D058848:Receptors, Purinergic P2X4 / Q000502:physiology; D058486:Receptors, Purinergic P2X7 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000008:administration & dosage; D013929:Thromboxane B2 / Q000096:biosynthesis
chemical_list: D018836:Inflammation Mediators; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D058911:Purinergic P2X Receptor Agonists; D058920:Purinergic P2X Receptor Antagonists; D058848:Receptors, Purinergic P2X4; D058486:Receptors, Purinergic P2X7; D011994:Recombinant Proteins; D007975:Leukotriene B4; D013929:Thromboxane B2; D000255:Adenosine Triphosphate; D051546:Cyclooxygenase 2; D015232:Dinoprostone