Identification of endogenous surrogate ligands for human P2Y12 receptors by in silico and in vitro methods

Nonaka, Y.; Hiramoto, Takeshi; Fujita, Norihisa

doi:10.1016/j.bbrc.2005.09.052

Cited by 102 publications

(102 citation statements)

References 30 publications

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“…On the other hand, although LTE 4 has only weak affinity for CysLT 1 , the enhancing effect of LTE 4 was inhibited by the CysLT 1 antagonist montelukast, suggesting that either LTE 4 can activate CysLT 1 when expressed endogenously in a Th2 cell environment or that montelukast has additional activities that are CysLT 1 -independent. It has been proposed that both montelukast and LTE 4 may interact with the P2Y-like receptors, LTE 4 acting as an agonist (41,42) and montelukast as an antagonist (43). However, treatment of Th2 cells with 2MeS, a selective antagonist of P2Y 12 , did not reduce significantly the enhancing effect of LTE 4 , indicating that P2Y 12 does not mediate the effect of LTE 4 .…”

Section: Discussionmentioning

confidence: 99%

“…The enhancing effect of LTE 4 was not mediated by P2Y 12 receptor but by a receptor that was partially sensitive to PTX It has also been reported that LTE 4 can act as an agonist at the P2Y 12 receptor (41,42) and that montelukast can antagonize some P2Y receptors (43), although the effect of montelukast has not been tested on P2Y 12 . The expression of P2Y 12 can be detected in human Th2 cells, but the level of this receptor is much lower than that seen with CysLT 1 (Fig.…”

Section: Cyslts Do Not Interact With Crth2 Directlymentioning

confidence: 97%

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Leukotriene E4 Activates Human Th2 Cells for Exaggerated Proinflammatory Cytokine Production in Response to Prostaglandin D2

Xue

Barrow

Fleming

et al. 2012

The Journal of Immunology

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PGD2 exerts a number of pro-inflammatory responses through a high affinity interaction with chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) and has been detected at high concentrations at sites of allergic inflammation. Since cysteinyl leukotrienes (cysLTs) are also produced during the allergic response we investigated the possibility that cysLTs may modulate the response of human Th2 cells to PGD2. PGD2 induced concentration-dependent Th2 cytokine production in the absence of TCR stimulation. Leukotrienes D4 (LTD4) and E4 (LTE4) also stimulated the cytokine production but were much less active than PGD2. However, when combined with PGD2, cysLTs caused a greater than additive enhancement of the response, with LTE4 being most effective in activating Th2 cells. LTE4 enhanced calcium mobilisation in response to PGD2 in Th2 cells without affecting endogenous PGD2 production or CRTH2 receptor expression. The effect of LTE4 was inhibited by montelukast but not by the P2Y12 antagonistmethylthioadenosine 5′-monophosphate. The enhancing effect was also evident with endogenous cysLTs produced from immunologically activated mast cells since inhibition of cysLT action by montelukast or cysLT sythesis by MK886, an inhibitor of 5-LO-activating protein, reduced the response of Th2 cells to the levels produced by PGD2 alone. These findings reveal that cysLTs, in particular LTE4, have a significant pro-inflammatory impact on T cells and demonstrate their effects on Th2 cells are mediated by a montelukast-sensitive receptor.

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Section: Discussionmentioning

confidence: 99%

Section: Cyslts Do Not Interact With Crth2 Directlymentioning

confidence: 97%

Leukotriene E4 Activates Human Th2 Cells for Exaggerated Proinflammatory Cytokine Production in Response to Prostaglandin D2

Xue

Barrow

Fleming

et al. 2012

The Journal of Immunology

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“…23,26,27 The relative insensitivity of either CysLT1 or CysLT2 receptors to LTE 4 , in contrast to the sensitivity of AERD subjects to this lipid mediator, led to the exploration for and ultimate identification of additional CysLT receptors that selectively respond to LTE 4 . [28][29][30] CysLT type 1 receptors are prominently expressed on airway smooth muscle, 31 and these receptors do mediate much of the CysLT-induced bronchospasm associated with aspirin challenges or desensitizations, [32][33][34][35] as evinced by the ability of leukotriene receptor antagonists to attenuate much of the bronchospasm that occurs with these procedures. Thus, AERD is characterized by enhanced sensitivity to leukotrienes, reflecting in part the overexpression of CysLT1 receptors.…”

Section: Cysteinyl Leukotriene Overproduction and Overresponsiveness mentioning

confidence: 99%

Factors Driving the Aspirin Exacerbated Respiratory Disease Phenotype

Steinke

Borish

2015

Am J Rhinol�Allergy

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“…Because LTE 4 shows negligible activity at CysLT1R and CysLT2R, its biological effects are likely mediated by a third, elusive receptor, which was tentatively identified with P2Y 12 , based on computer modelling and the demonstration that LTE 4 signals through P2Y 12 in transfected cells (72). However, more recently GPR99 was identified as the elusive receptor for LTE 4 (67).…”

Section: Allergic Bronchial Asthmamentioning

confidence: 99%

The platelet P2 receptors in inflammation

Cattaneo¹

2015

Hamostaseologie

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SummaryIn addition to their well characterized and established role in haemostasis and thrombosis, platelets contribute to the pathogenesis of inflammation. Adenine nucleotides are signalling molecules that regulate the function of virtually every cell in the body, by interacting with P2 receptors. Their important role in inflammation is well established. In the last few years, the pro-inflammatory roles of adenine nucleotides interacting with their platelet P2 receptors has emerged. In particular, it was shown that the platelet P2Y 12 receptor for ADP significantly contributed to the proinflammatory effects of cysteinyl leukotrienes (CysLT) in experimental models of asthma in mice. More importantly, it was recently shown that P2Y 12 variants were associated with lung function in a large family-based asthma cohort and that the P2Y 12 antagonist prasugrel tended to decrease bronchial hyper-reactivity to mannitol in patients with allergic bronchial asthma in a randomized, placebo controlled trial. Conclusion: These data strongly suggest that P2Y 12 may represent an important pharmacological target for the treatment of patients with allergic bronchial asthma. Schlüsselwörter

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Identification of endogenous surrogate ligands for human P2Y12 receptors by in silico and in vitro methods

Cited by 102 publications

References 30 publications

Leukotriene E4 Activates Human Th2 Cells for Exaggerated Proinflammatory Cytokine Production in Response to Prostaglandin D2

Leukotriene E4 Activates Human Th2 Cells for Exaggerated Proinflammatory Cytokine Production in Response to Prostaglandin D2

Factors Driving the Aspirin Exacerbated Respiratory Disease Phenotype

The platelet P2 receptors in inflammation

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