title: Selective induction of endothelial P2Y6 nucleotide receptor promotes vascular inflammation.
abstract: During a systemic inflammatory response endothelial-expressed surface molecules have been strongly implicated in orchestrating immune responses. Previous studies have shown enhanced extracellular nucleotide release during acute inflammatory conditions. Therefore, we hypothesized that endothelial nucleotide receptors could play a role in vascular inflammation. To address this hypothesis, we performed screening experiments and exposed human microvascular endothelia to inflammatory stimuli, followed by measurements of P2Y or P2X transcriptional responses. These studies showed a selective induction of the P2Y(6) receptor (> 4-fold at 24 hours). Moreover, studies that used real-time reverse transcription-polymerase chain reaction, Western blot analysis, or immunofluorescence confirmed time- and dose-dependent induction of P2Y(6) with tumor necrosis factor α or Lipopolysaccharide (LPS) stimulation in vitro and in vivo. Studies that used MRS 2578 as P2Y(6) receptor antagonist showed attenuated nuclear factor κB reporter activity and proinflammatory gene expression in human microvascular endothelial cells in vitro. Moreover, pharmacologic or genetic in vivo studies showed attenuated inflammatory responses in P2Y(6)(-/-) mice or after P2Y(6) antagonist treatment during LPS-induced vascular inflammation. These studies show an important contribution of P2Y(6) signaling in enhancing vascular inflammation during systemic LPS challenge and implicate the P2Y(6) receptor as a therapeutic target during systemic inflammatory responses.
authors.affiliation: Department of Anesthesiology and Intensive Care Medicine, University of Tübingen, Tübingen, Germany.
authors.forename: Ann-Kathrin
authors.initials: AK
authors.lastname: Riegel
authors.forename: Marion
authors.initials: M
authors.lastname: Faigle
authors.forename: Stephanie
authors.initials: S
authors.lastname: Zug
authors.forename: Peter
authors.initials: P
authors.lastname: Rosenberger
authors.forename: Bernard
authors.initials: B
authors.lastname: Robaye
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Boeynaems
authors.forename: Marco
authors.initials: M
authors.lastname: Idzko
authors.forename: Holger K
authors.initials: HK
authors.lastname: Eltzschig
mesh_terms: D000818:Animals; D042783:Endothelial Cells; D004730:Endothelium, Vascular / Q000473:pathology*; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000209:etiology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D018048:Receptors, Purinergic P2 / Q000235:genetics* / Q000378:metabolism; D058469:Receptors, Purinergic P2X / Q000235:genetics; D058470:Receptors, Purinergic P2Y / Q000235:genetics; D015533:Transcriptional Activation
chemical_list: D008070:Lipopolysaccharides; D018048:Receptors, Purinergic P2; D058469:Receptors, Purinergic P2X; D058470:Receptors, Purinergic P2Y; C099845:purinoceptor P2Y6