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 Ca2+ 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.

Leukotriene B4 Modulates P2X7 Receptor–MediatedLeishmania amazonensisElimination in Murine Macrophages

“…Moreover, other studies have shown that lipid mediators can interact with P2Y receptors. Recently, it was reported that PGE 2 selectively impairs P2Y receptor-mediated Ca 2+ mobilization (31). Other works have demonstrated that pulmonary inflammation mediated by LTE 4 requires P2Y12 receptor (32).…”

Prostaglandin E2-mediated adenosinergic effects on CD14+cells: Self-amplifying immunosuppression in cancer

“…We demonstrate here that CD73 upregulation on CD14 C cells by sPE is blocked by inhibiting its receptors, EP2 and EP4, confirming the role of PGE 2 in the regulation of the adenosinergic pathway in mesothelioma. PGE 2 has also been shown to impair purinergic signaling by ATP in macrophages 36 which suggests that in the presence of PGE 2 , extracellular ATP is preferentially undergoing hydrolysis by myeloid cells.…”

Modulation of Voltage-Dependent and Inward Rectifier Potassium Channels by 15-Epi-Lipoxin-A4 in Activated Murine Macrophages: Implications in Innate Immunity

“…The fluorescence was recorded at 510 nm in an LS50B Perkin-Elmer spectrofluorometer (PerkinElmer, Norwalk, CT) provided with continuous stirring and using a dual excitation source at 340 and 380 nm. The maximal and minimal fluorescence of the assay were determined for each sample after addition of 1% SDS and 5 mM EGTA (pH 9), respectively (29).…”