title: Selective impairment of P2Y signaling by prostaglandin E2 in macrophages: implications for Ca2+-dependent responses.
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.
authors.affiliation: Departamento 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.
authors.forename: Paqui G
authors.initials: PG
authors.lastname: Través
authors.forename: María
authors.initials: M
authors.lastname: Pimentel-Santillana
authors.forename: Luz María G
authors.initials: LM
authors.lastname: Carrasquero
authors.forename: Raquel
authors.initials: R
authors.lastname: Pérez-Sen
authors.forename: Esmerilda G
authors.initials: EG
authors.lastname: Delicado
authors.forename: Alfonso
authors.initials: A
authors.lastname: Luque
authors.forename: Manuel
authors.initials: M
authors.lastname: Izquierdo
authors.forename: Paloma
authors.initials: P
authors.lastname: Martín-Sanz
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Miras-Portugal
authors.forename: Lisardo
authors.initials: L
authors.lastname: Boscá
mesh_terms: D000818:Animals; D002118:Calcium / Q000502:physiology*; D020013:Calcium Signaling / Q000276:immunology; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000096:biosynthesis / Q000235:genetics; D015232:Dinoprostone / Q000378:metabolism / Q000502:physiology*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007424:Intracellular Fluid / Q000276:immunology / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D058470:Receptors, Purinergic P2Y / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D058470:Receptors, Purinergic P2Y; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D002118:Calcium