Distribution of P2Y receptor subtypes on haematopoietic cells

Jin, Jianguo; Dasari, Venkat R.; Sistare, Frank D.; Kunapuli, Satya P.

doi:10.1038/sj.bjp.0701665

Cited by 113 publications

(109 citation statements)

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“…Here we found that these leukotriene antagonists also inhibit the effects of nucleotides acting at P2Y receptors in dU937 cells, which are known to express a number of nucleotide receptors, such as P2Y 2 or P2Y 4 [30]. In an effort to characterize the P2 receptor subtypes subject to negative modulation by CysLT 1 receptor antagonists we studied the interactions of these compounds in human P2Y 1 6 receptor were grown at 37 °C in a humidified incubator with 5% CO 2 /95% air in Dulbecco's modified Eagle's medium (JRH Biosciences, Inc., Lenexa, KS, USA) and F12 (1:1) supplemented with 10% FBS, 100 units/ml penicillin, 100 μg/ml streptomycin and 2 mM Lglutamine.…”

Section: Introductionmentioning

confidence: 67%

CysLT1 leukotriene receptor antagonists inhibit the effects of nucleotides acting at P2Y receptors

Mamedova

Capra

Accomazzo

et al. 2005

Biochemical Pharmacology

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Montelukast and pranlukast are orally active leukotriene receptor antagonists selective for the CysLT 1 receptor. Conversely, the hP2Y 1,2,4,6,11,12,13,14 receptors represent a large family of GPCRs responding to either adenine or uracil nucleotides, or to sugar-nucleotides. Montelukast and pranlukast were found to inhibit nucleotide-induced calcium mobilization in a human monocyte-macrophage like cell line, DMSO-differentiated U937 (dU937). Montelukast and pranlukast inhibited the effects of UTP with IC 50 values of 7.7 and 4.3 μM, respectively, and inhibited the effects of UDP with IC 50 values of 4.5 and 1.6 μM, respectively, in an insurmountable manner. Furthermore, ligand binding studies using [ 3 H]LTD 4 excluded the possibility of orthosteric nucleotide binding to the CysLT 1 receptor. dU937 cells were shown to express P2Y 2 , P2Y 4 , P2Y 6 , P2Y 11 , P2Y 13 and P2Y 14 receptors. Therefore, these antagonists were studied functionally in a heterologous expression system for the human P2Y receptors. In 1321N1 astrocytoma cells stably expressing human P2Y 1,2,4,6 receptors, CysLT 1 antagonists inhibited both the P2Y agonist-induced activation of phospholipase C and intracellular Ca 2+ mobilization. IC 50 values at P2Y 1 and P2Y 6 receptors were <1 μM. In control astrocytoma cells expressing an endogenous M3 muscarinic receptor, 10 μM montelukast had no effect on the carbachol-induced rise in intracellular Ca 2+ . These data demonstrated that CysLT 1 receptor antagonists interact functionally with signaling pathways of P2Y receptors, and this should foster the study of possible implications for the clinical use of these compounds in asthma or in other inflammatory conditions.

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Section: Introductionmentioning

confidence: 67%

CysLT1 leukotriene receptor antagonists inhibit the effects of nucleotides acting at P2Y receptors

Mamedova

Capra

Accomazzo

et al. 2005

Biochemical Pharmacology

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“…Previous studies by us and others have reported the presence of P2Y 6 transcripts in human spleen, placenta, thymus, small intestine, and leukocytes (neutrophils, lymphocytes, and monocytes) suggesting that P2Y 6 plays a role in immune defenses (7,10). However, the physiological responses mediated by UDP and P2Y 6 are not known.…”

mentioning

confidence: 86%

P2Y6 Nucleotide Receptor Mediates Monocyte Interleukin-8 Production in Response to UDP or Lipopolysaccharide

Warny¹,

Aboudola²,

Robson³

et al. 2001

Journal of Biological Chemistry

142

133

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Extracellular nucleotides are autocrine and paracrine cellular mediators that signal through P2 nucleotide receptors. Monocytic cells express several P2Y receptors but the role of these G protein-coupled receptors in monocytes is not known. Here, we present evidence that P2Y 6 regulates chemokine production and release in monocytes. We find that UDP, a selective P2Y 6 agonist, stimulates interleukin (IL)-8 release in human THP-1 monocytic cells whereas other nucleotides are relatively inactive. P2 receptor antagonists or P2Y 6 antisense oligonucleotides inhibit IL-8 release induced by UDP. Furthermore, UDP specifically activated IL-8 production in astrocytoma 1321N1 cells transfected with human P2Y 6 . Since lipopolysaccharide has been suggested to activate P2 receptors via nucleotide release, we tested whether IL-8 production stimulated by lipopolysaccharide might result from P2Y 6 activation. P2 antagonists or apyrase, an enzyme which hydrolyzes nucleotides including UDP, inhibit IL-8 production induced by lipopolysaccharide but not by other stimuli. Furthermore, IL-8 gene expression activated by lipopolysaccharide is enhanced by P2Y 6 overexpression and inhibited by P2Y 6 antisense oligonucleotides. Thus, UDP activates IL-8 production via P2Y 6 in monocytic cells. Furthermore, lipopolysaccharide mediates IL-8 production at least in part by autocrine P2Y 6 activation. These findings indicate a novel role for P2Y 6 in innate immune defenses.

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“…P2 receptors are divided into two subfamilies: the G-protein-coupled receptors (P2Y 1,2,4,6,[11][12][13][14] ) and the ligand-gated ion channels (P2X 1-7 ). The P2Y subtypes differ in their selectivity toward adenine (ATP, ADP) and uracil nucleotides (UTP, UDP) while all P2X receptors are activated by ATP [10,11].…”

Section: Introductionmentioning

confidence: 99%

“…The P2Y subtypes differ in their selectivity toward adenine (ATP, ADP) and uracil nucleotides (UTP, UDP) while all P2X receptors are activated by ATP [10,11]. Human primary monocytes and monocytic cell lines (THP-1 and U937) express the mRNA of various P2 receptors of which P2X 1,7 and P2Y 2,6,11 are common to all these cells [12,13]. There is growing evidence indicating that P2 receptors mediate some important proinflammatory responses activated by the stimulation of monocytes/macrophages with PAMP.…”

Section: Introductionmentioning

confidence: 99%

Concomitant activation of P2Y₂ and P2Y₆ receptors on monocytes is required for TLR1/2‐induced neutrophil migration by regulating IL‐8 secretion

et al. 2009

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Extracellular nucleotides regulate a variety of cellular responses involved in inflammation via the activation of P2 receptors. Here, we show that nucleotides regulate TLR2-induced neutrophil migration both in vivo and in vitro. The nucleotide scavenger apyrase inhibited neutrophil recruitment in murine air pouches injected with the TLR2 agonist Pam 3 CSK 4 . In agreement, the supernatants of either human primary monocytes or monocytic cells (THP-1 and U937) treated with Pam 3 CSK 4 recruited significantly fewer neutrophils when the former cells were treated in the presence of apyrase. As demonstrated with inhibitory Ab, these supernatants induced neutrophil migration due to IL-8 secretion. In addition, IL-8 secretion was markedly diminished by the non-selective P2 receptor antagonists reactive blue 2 and suramin, and by a selective P2Y 6 antagonist, MRS2578. Selective antagonists of P2Y 1 (MRS2500) and P2Y 11 (NF157) did not affect IL-8 release. The knockdown of either P2Y 2 or P2Y 6 with specific shRNA diminished IL-8 secretion from Pam 3 CSK 4 -treated THP-1 cells. Altogether, these results show that extracellular nucleotides, via P2Y 2 and P2Y 6 receptors, regulate neutrophil migration by controlling TLR2-induced IL-8 release from human monocytes. In line with our previous work on TLR4, this study further supports the importance of nucleotides in bacterial-induced neutrophil migration.Key words: Cell trafficking . Human monocytes . Inflammation . Neutrophils . Pam 3 CSK 4 IntroductionMonocytes play an important role in immune defences against invading bacteria and viruses via TLR activation [1]. TLR recognize highly conserved structural motifs expressed by microbes called PAMP. Monocytes express various TLR including TLR4 (that is activated by LPS, a cell wall component of Gramnegative bacteria), TLR2 (activated by peptidoglycan and lipopeptide, components of Gram-positive bacteria), TLR5 (activated by the bacterial flagellin) and TLR7/8 (activated by single-stranded viral RNA) [2][3][4][5]. In response to TLR activation by PAMP, monocytes release various cytokines and chemokines that orchestrate the innate immune responses [6][7][8]. For example, these cells secrete large amounts of the chemokine IL-8 that plays a major role in neutrophil recruitment at sites of infection [9].In addition to TLR, monocytes abundantly express P2 receptors that are activated by extracellular nucleotides. P2 receptors are divided into two subfamilies: the G-protein-coupled receptors (P2Y 1,2,4,6,[11][12][13][14] ) and the ligand-gated ion channels (P2X 1-7 ). The P2Y subtypes differ in their selectivity toward adenine (ATP, ADP) and uracil nucleotides (UTP, UDP) while all P2X receptors are activated by ATP [10,11]. Human primary monocytes and monocytic cell lines (THP-1 and U937) express the mRNA of various P2 receptors of which P2X 1,7 and P2Y 2,6,11 are common to all these cells [12,13]. There is growing evidence indicating that Results Extracellular nucleotides are involved in Pam 3 CSK 4 -induced neutrophil migration in vi...

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Distribution of P2Y receptor subtypes on haematopoietic cells

Abstract: 1 RT ± PCR-southern hybridization analyses with radiolabelled P2Y receptor cDNAs as probes indicated that the peripheral blood leukocytes and the human umbilical vein endothelial cells express P2Y 1 , P2Y 2 , P2Y 4 and P2Y 6 receptors.

Cited by 113 publications

References 44 publications

CysLT1 leukotriene receptor antagonists inhibit the effects of nucleotides acting at P2Y receptors

CysLT1 leukotriene receptor antagonists inhibit the effects of nucleotides acting at P2Y receptors

P2Y6 Nucleotide Receptor Mediates Monocyte Interleukin-8 Production in Response to UDP or Lipopolysaccharide

Concomitant activation of P2Y₂ and P2Y₆ receptors on monocytes is required for TLR1/2‐induced neutrophil migration by regulating IL‐8 secretion

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Distribution of P2Y receptor subtypes on haematopoietic cells

Abstract: 1 RT ± PCR-southern hybridization analyses with radiolabelled P2Y receptor cDNAs as probes indicated that the peripheral blood leukocytes and the human umbilical vein endothelial cells express P2Y 1 , P2Y 2 , P2Y 4 and P2Y 6 receptors.

Cited by 113 publications

References 44 publications

CysLT1 leukotriene receptor antagonists inhibit the effects of nucleotides acting at P2Y receptors

CysLT1 leukotriene receptor antagonists inhibit the effects of nucleotides acting at P2Y receptors

P2Y6 Nucleotide Receptor Mediates Monocyte Interleukin-8 Production in Response to UDP or Lipopolysaccharide

Concomitant activation of P2Y2 and P2Y6 receptors on monocytes is required for TLR1/2‐induced neutrophil migration by regulating IL‐8 secretion

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Concomitant activation of P2Y₂ and P2Y₆ receptors on monocytes is required for TLR1/2‐induced neutrophil migration by regulating IL‐8 secretion