Selective induction of endothelial P2Y6 nucleotide receptor promotes vascular inflammation
Standard
Selective induction of endothelial P2Y6 nucleotide receptor promotes vascular inflammation. / Riegel, Ann-Kathrin; Faigle, Marion; Zug, Stephanie; Rosenberger, Peter; Robaye, Bernard; Boeynaems, Jean-Marie; Idzko, Marco; Eltzschig, Holger K.
in: BLOOD, Jahrgang 117, Nr. 8, 24.02.2011, S. 2548-55.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Selective induction of endothelial P2Y6 nucleotide receptor promotes vascular inflammation
AU - Riegel, Ann-Kathrin
AU - Faigle, Marion
AU - Zug, Stephanie
AU - Rosenberger, Peter
AU - Robaye, Bernard
AU - Boeynaems, Jean-Marie
AU - Idzko, Marco
AU - Eltzschig, Holger K
PY - 2011/2/24
Y1 - 2011/2/24
N2 - 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.
AB - 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.
KW - Animals
KW - Endothelial Cells
KW - Endothelium, Vascular
KW - Gene Expression Profiling
KW - Humans
KW - Inflammation
KW - Lipopolysaccharides
KW - Mice
KW - Mice, Knockout
KW - Receptors, Purinergic P2
KW - Receptors, Purinergic P2X
KW - Receptors, Purinergic P2Y
KW - Transcriptional Activation
KW - Journal Article
KW - Research Support, N.I.H., Extramural
U2 - 10.1182/blood-2010-10-313957
DO - 10.1182/blood-2010-10-313957
M3 - SCORING: Journal article
C2 - 21173118
VL - 117
SP - 2548
EP - 2555
JO - BLOOD
JF - BLOOD
SN - 0006-4971
IS - 8
ER -