Prostaglandin E2 suppresses allergic sensitization and lung inflammation by targeting the E prostanoid 2 receptor on T cells

Abstract

Background Endogenous prostanoids have been suggested to modulate sensitization during experimental allergic asthma, but the specific role of prostaglandin E2 (PGE2) or of specific E prostanoid (EP) receptors is not known. Objective Here we tested the role of EP2 signaling in allergic asthma. Methods Wild type (WT) and EP2−/− mice were subjected to ovalbumin sensitization and acute airway challenge. The PGE2 analog misoprostol was administered during sensitization in both genotypes. In vitro culture of splenocytes and of flow-sorted dendritic cells and T cells defined the mechanism by which EP2 exerted its protective effect. Adoptive transfer of WT and EP2−/− CD4 T cells was used to validate the importance of EP2 expression on T cells. Results As compared to WT mice, EP2−/− mice had exaggerated airway inflammation in this model. Splenocytes and lung lymph node cells from sensitized EP2−/− mice produced more IL-13 than did WT cells, suggesting increased sensitization. In WT but not EP2−/− mice, subcutaneous administration of a stable PGE2 analog during sensitization inhibited allergic inflammation. PGE2 decreased cytokine production and inhibited STAT6 phosphorylation by CD3/CD28-stimulated CD4pos T cells. Co-culture of flow cytometry-sorted splenic CD4pos T cells and CD11cpos dendritic cells from WT or EP2−/− mice suggested that the increased IL-13 production in EP2−/− mice was due to the lack of EP2 specifically on T cells. Adoptive transfer of CD4pos EP2−/− T cells caused greater cytokine production in the lungs of WT mice than did transfer of WT CD4pos T cells. Conclusion We conclude that the PGE2-EP2 axis is an important endogenous brake on allergic airway inflammation, primarily targets T cells, and its agonism represents a potential novel therapeutic approach to asthma.

Culture medium from TNF-α–stimulated mesenchymal stem cells attenuates allergic conjunctivitis through multiple antiallergic mechanisms

“…The therapeutic effects of PGE 2 or its analogs on allergic inflammation have been previously described [34][35][36] ; however, conflicting results with respect to its efficacy have been obtained, depending on the receptor subtype. [37][38][39][40][41][42] For example, PGE 2 suppresses allergic inflammation mediated through EP3 or EP2 37-39 while triggering inflammatory responses through EP4 or EP1. [40][41][42] These discrepancies might limit the clinical application of PGE 2 and its analogs in the treatment of allergic diseases.…”

Resident Alveolar Macrophages Suppress, whereas Recruited Monocytes Promote, Allergic Lung Inflammation in Murine Models of Asthma

“…OVA-induced acute allergic inflammation was elicited as previously described by intraperitoneal sensitization with 20 µg of OVA (Sigma-Aldrich, St. Louis, MO) mixed with 2 mg of alum (Thermo Fisher Scientific, Waltham, MA) [14] on day 0 followed by two nebulizer-delivered airway challenges with 1 % OVA on days 7 and 8 [15]. House dust mite (HDM)-induced inflammation utilized extracts of Dermatophagoides pteronyssinus mites (Greer, Lenoir, NC) crushed with a mortar and pestle.…”

Expression Profiles of Prostaglandin E2 Receptor Subtypes in Aspirin Tolerant Adult Chinese with Chronic Rhinosinusitis

“…As mentioned, overexpression of the EP1 receptor should lead to increased proinflammatory mediator release from the infiltrating eosinophils, monocytes and/or macrophages, lymphocytes, and mast cells in polyp tissues. 13,35 Some mediators such as interleukin (IL)-3, IL-5, IL-13, granulocyte-macrophage colony stimulating factor and eotaxin have been shown to promote the accumulation of eosinophils in eosinophilic CRSwNP. 3,36 We, therefore, conjecture that enhanced EP receptor expression might correlate with the exaggerated increase in eosinophils.…”