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Selective impairment of P2Y signaling by prostaglandin E2 in macrophages: implications for Ca2+-dependent responses
Paqui G Través1, María Pimentel-Santillana, Luz María G Carrasquero
1Departamento de Bioquímica y Biología Molecular IV, Facultad de Veterinaria e Instituto Universitario de Investigación en Neuroquímica, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Universidad Complutense Madrid, 28040 Madrid, Spain.
Abstract:
Extracellular nucleotides have been recognized as important modulators of inflammation via their action on specific pyrimidine receptors (P2). This regulation coexists with the temporal framework of proinflammatory and proresolution mediators released by the cells involved in the inflammatory response, including macrophages. Under proinflammatory conditions, the expression of cyclooxygenase-2 leads to the release of large amounts of PGs, such as PGE2, that exert their effects through EP receptors and other intracellular targets. The effect of these PGs on P2 receptors expressed in murine and human macrophages was investigated. In thioglycollate-elicited and alternatively activated macrophages, PGE2 selectively impairs P2Y but not P2X7 Ca(2+) mobilization. This effect is absent in LPS-activated cells and is specific for PGE2 because it cannot be reproduced by other PGs with cyclopentenone structure. The inhibition of P2Y responses by PGE2 involves the activation of nPKCs (PKCε) and PKD that can be abrogated by selective inhibitors or by expression of dominant-negative forms of PKD. The inhibition of P2Y signaling by PGE2 has an impact on the cell migration elicited by P2Y agonists in thioglycollate-elicited and alternatively activated macrophages, which provide new clues to understand the resolution phase of inflammation, when accumulation of PGE2, anti-inflammatory and proresolving mediators occurs.
Insights
Prostaglandin E2 (PGE2) specifically inhibits calcium (Ca2+) signaling through P2Y receptors in certain macrophages. This finding offers new insights into how inflammation resolves.
Area of Science:
- Immunology
- Cell Biology
- Pharmacology
Background:
- Extracellular nucleotides modulate inflammation via purinergic (P2) receptors.
- Macrophages release pro-inflammatory and pro-resolution mediators, including prostaglandins (PGs).
- Prostaglandin E2 (PGE2), produced via cyclooxygenase-2, acts on EP receptors and influences inflammatory processes.
Purpose of the Study:
- To investigate the effects of PGs, specifically PGE2, on P2 receptors in macrophages.
- To elucidate the signaling pathways involved in PGE2-mediated P2 receptor modulation.
- To understand the impact of this modulation on macrophage functions, such as cell migration.
Main Methods:
- Investigated P2 receptor-mediated calcium (Ca2+) mobilization in thioglycollate-elicited and alternatively activated murine and human macrophages.
- Assessed the effect of PGE2 and other PGs on P2Y and P2X7 receptor activity.
- Utilized selective inhibitors and dominant-negative constructs to study the involvement of protein kinase C (PKC) and protein kinase D (PKD) signaling pathways.
- Examined the impact of PGE2 on P2Y-agonist-elicited macrophage migration.
Main Results:
- PGE2 selectively impaired P2Y receptor-mediated Ca2+ mobilization in thioglycollate-elicited and alternatively activated macrophages, but not in LPS-activated cells.
- This inhibitory effect was specific to PGE2 and not observed with other cyclopentenone PGs.
- PGE2-induced inhibition of P2Y signaling involved the activation of novel protein kinase C (nPKC, specifically PKCε) and PKD.
- Inhibition of P2Y signaling by PGE2 significantly impacted P2Y-agonist-elicited macrophage migration.
Conclusions:
- PGE2 plays a critical role in modulating purinergic signaling in specific macrophage populations.
- The findings reveal a novel mechanism involving PKC and PKD pathways through which PGE2 regulates P2Y receptor function.
- This PGE2-mediated inhibition of P2Y signaling offers new insights into the resolution phase of inflammation, particularly concerning macrophage behavior and mediator accumulation.
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