PGE₂ deficiency predisposes to anaphylaxis by causing mast cell hyperresponsiveness.

Abstract

Reduced levels of prostaglandin E₂ (PGE₂) contribute to aspirin-induced hypersensitivity. COX inhibitors are also frequent cofactors in anaphylaxis. Whether alterations in the PGE₂ system contribute to anaphylaxis independently of COX inhibitor intake is unclear. Our aim was to test the hypothesis that relative PGE₂ deficiency predisposes to anaphylaxis. Sera from 48 patients with anaphylaxis and 27 healthy subjects were analyzed for PGE₂ levels and correlated against severity; 9α,11β-PGF₂ and PGI₂ metabolites were measured for control purposes. PGE₂ stabilization by 15-hydroxyprostaglandin dehydrogenase inhibitor or EP2 or EP4 receptor agonists were used in a murine model of passive systemic anaphylaxis. FcεRI-triggered mediator release was determined in bone marrow-derived cultured mast cells (MCs) and human skin-derived MCs. Signaling was studied by Western blot analysis. Patients with anaphylaxis were characterized by markedly reduced PGE₂ levels vis-à-vis healthy subjects, whereas prostacyclin metabolite levels were diminished only weakly, and 9α,11β-PGF₂ levels conversely increased. PGE₂ was negatively correlated with severity. Lower PGE₂ levels and higher susceptibility to anaphylaxis were also found in C57BL/6 mice vis-à-vis in Balb/c mice. Stabilization of PGE₂ level by 15-hydroxyprostaglandin dehydrogenase inhibitor protected mice against anaphylaxis. Exogenous PGE₂ attenuated bone marrow-derived cultured MC activation through EP2 and EP4 receptors. EP2 and EP4 agonism also curbed FcεRI-mediated degranulation of human MCs. Mechanistically, PGE₂ interfered with the phosphorylation of phospholipase C gamma-1 and extracellular signal-regulated kinase. Homeostatic levels of PGE₂ attenuate MC activation via EP2/EP4 and protect against anaphylaxis. Relative deficiency of PGE₂ predisposes to anaphylaxis in humans and mice, whereas PGE₂ stabilization protects against anaphylactic reactions.