E-prostanoid 2 receptors dampen mast cell degranulation via cAMP/PKA-mediated suppression of IgE-dependent signaling

Mariona Serra-Pages, Ana Olivera, Rosa Torres, César Picado, Fernando de Mora, Juan Rivera

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Resum

The experimental administration of PGE2 for the treatment of asthma dampens clinical symptoms, and similar efficacy has been found in dust mite-induced hypersensitivity reactions in animal models. Here, we investigate the mechanism by which PGE2 mediates suppression of MC degranulation. We find that the effect of PGE2 on FcεRI-dependent MC degranulation varies from activating to suppressing, depending on the relative ratio of EP2 to EP3 expression on these cells with suppression evident only in cells having increased EP2 to EP3 expression. Consistent with a role for EP2 in suppressing MC responses in vitro, we found that a selective EP2 agonist, Butaprost, inhibited MC-mediated FcRI-induced immediate hypersensitivity in a model of PCA. EP2 engagement on MCs increased cAMP production and inhibited FcRI-mediated calcium influx. In addition, it also decreased the extent of FcRI-induced Fyn kinase activity, leading to decreased phosphorylation of key signaling molecules such as Gab2 and Akt. Treatment with an antagonist of cAMP or shRNA downregulation of PKA (the principal intracellular target of cAMP) reversed the EP2-mediated inhibitory effect on MC degranulation and restored calcium influx and phosphorylation of Akt. Collectively, the findings demonstrate that EP2 suppresses the Fyn-mediated signals that are central to FcRI-dependent MC degranulation, suggesting that engagement of the EP2 on MCs may be beneficial in dampening allergic responses.
Idioma originalEnglish
Pàgines (de-a)1155-1165
RevistaJournal of Leukocyte Biology
Volum92
DOIs
Estat de la publicacióPublicada - 1 de des. 2012

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