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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / administration & dosage
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Adenosine Triphosphate / metabolism
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Animals
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Calcium Signaling
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Cyclooxygenase 2 / metabolism
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Dinoprostone / physiology*
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Fever / etiology*
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Fever / physiopathology*
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Humans
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In Vitro Techniques
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Inflammation Mediators / physiology
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Injections, Intraperitoneal
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Interleukin-1beta / administration & dosage
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Interleukin-1beta / physiology*
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Leukotriene B4 / biosynthesis
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Lipopolysaccharides / administration & dosage
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MAP Kinase Signaling System
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Macrophages / drug effects
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Macrophages / physiology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Purinergic P2X Receptor Agonists / pharmacology
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Purinergic P2X Receptor Antagonists / pharmacology
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Receptors, Purinergic P2X4 / physiology
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Receptors, Purinergic P2X7 / deficiency
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Receptors, Purinergic P2X7 / genetics
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Receptors, Purinergic P2X7 / physiology*
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Recombinant Proteins / administration & dosage
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Thromboxane B2 / biosynthesis
Substances
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Inflammation Mediators
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Interleukin-1beta
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Lipopolysaccharides
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Purinergic P2X Receptor Agonists
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Purinergic P2X Receptor Antagonists
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Receptors, Purinergic P2X4
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Receptors, Purinergic P2X7
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Recombinant Proteins
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Leukotriene B4
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Thromboxane B2
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Adenosine Triphosphate
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Cyclooxygenase 2
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Dinoprostone