title: Differential role of pannexin-1/ATP/P2X7axis in IL-1β release by human monocytes.
abstract: IL-1β release is integral to the innate immune system. The release of mature IL-1β depends on 2 regulated events: thede novoinduction of pro-IL-1β, generallyviaNF-κB-dependent transduction pathways; and the assembly and activation of the NLRP3 inflammasome. This latter step is reliant on active caspase-1, pannexin-1, and P2X7receptor activation. Pathogen-associated molecular patterns in gram-positive and gram-negative bacteria activate IL-1β release from immune cellsviaTLR2 and TLR4 receptors, respectively. We found that pro-IL-1β and mature IL-1β release from human monocytes is stimulated by the TLR2 agonists Pam3CSK4 or FSL-1, as well as the TLR4 agonist LPS in the absence of additional ATP. TLR2 agonists required pannexin-1 and P2X7receptor activation to stimulate IL-1β release. In contrast, IL-1β release stimulated by the TLR4 agonist LPS is independent of both pannexin-1 and P2X7activation. In the absence of exogenous ATP, P2X7activation requires endogenous ATP release, which occurs in some cellsviapannexin-1. In line with this, we found that LPS-stimulated human monocytes released relatively low levels of ATP, whereas cells stimulated with TLR2 agonists released high levels of ATP. These findings suggest that in human monocytes, both TLR2 and TLR4 signaling induce pro-IL-1β expression, but the mechanism by which they activate caspase-1 diverges at the level of the pannexin-1/ATP/P2X7axis.-Parzych, K., Zetterqvist, A. V., Wright, W. R., Kirkby, N. S., Mitchell, J. A., Paul-Clark, M. J. Differential role of pannexin-1/ATP/P2X7axis in IL-1β release by human monocytes.
authors.affiliation: Department of Cardiovascular Pharmacology, Vascular Biology, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Parzych
authors.affiliation: Department of Clinical Sciences, Lund University, Malmö, Sweden.
authors.forename: Anna V
authors.initials: AV
authors.lastname: Zetterqvist
authors.affiliation: Department of Cardiovascular Pharmacology, Vascular Biology, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: William R
authors.initials: WR
authors.lastname: Wright
authors.affiliation: Department of Cardiovascular Pharmacology, Vascular Biology, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Kirkby
authors.affiliation: Department of Cardiovascular Pharmacology, Vascular Biology, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Jane A
authors.initials: JA
authors.lastname: Mitchell
authors.affiliation: Department of Cardiovascular Pharmacology, Vascular Biology, National Heart and Lung Institute, Imperial College London, London, United Kingdom; m.paul-clark@imperial.ac.uk.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Paul-Clark
mesh_terms: D000255:Adenosine Triphosphate / Q000235:genetics / Q000378:metabolism*; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D017630:Connexins / Q000235:genetics / Q000378:metabolism*; D004075:Diglycerides / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D055666:Lipopeptides / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000235:genetics / Q000378:metabolism
chemical_list: D017630:Connexins; D004075:Diglycerides; C460864:FSL-1 lipoprotein, synthetic; D053583:Interleukin-1beta; D055666:Lipopeptides; D008070:Lipopolysaccharides; D009419:Nerve Tissue Proteins; D009842:Oligopeptides; C492764:PANX1 protein, human; C508075:Pam(3)CSK(4) peptide; D058486:Receptors, Purinergic P2X7; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D000255:Adenosine Triphosphate; D020170:Caspase 1
keywords: Toll-like receptors; inflammasome; innate immunity; potassium channels