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

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• 作者：Zbigniew Zas艂ona ; Katsuhide Okunishi ; Emilie Bourdonnay ; Racquel Domingo-Gonzalez ; Bethany B. Moore ; Nicholas W. Lukacs ; David M. Aronoff ; Marc Peters-Golden
• 关键词：Asthma ; allergic sensitization ; prostaglandin E2 ; CD4 T cells
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：February, 2014
• 年：2014
• 卷：133
• 期：2
• 页码：379-387.e1
• 全文大小：1417 K

文摘

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Background

Endogenous prostanoids have been suggested to modulate sensitization during experimental allergic asthma, but the specific role of prostaglandin (PG) E₂ 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^{鈭?鈭?/sup> mice were subjected to ovalbumin sensitization and acute airway challenge. The PGE₂ analog misoprostol was administered during sensitization in both genotypes. In聽vitro culture of splenocytes and flow-sorted dendritic cells and T cells defined the mechanism by which EP2 exerted its protective effect. Adoptive transfer of WT and EP2鈭?鈭?/sup> CD4 T cells was used to validate the importance of EP2 expression on T cells.}

Results

Compared with WT mice, EP2^{鈭?鈭?/sup> mice had exaggerated airway inflammation in this model. Splenocytes and lung lymph node cells from sensitized EP2鈭?鈭?/sup> mice produced more IL-13 than did WT cells, suggesting increased sensitization. In WT but not EP2鈭?鈭?/sup> mice, subcutaneous administration of misoprostol during sensitization inhibited allergic inflammation. PGE₂ decreased cytokine production and inhibited signal transducer and activator of transcription 6 phosphorylation by CD3/CD28-stimulated CD4+ T cells. Coculture of flow cytometry-sorted splenic CD4+ T cells and CD11c+ dendritic cells from WT or EP2鈭?鈭?/sup> mice suggested that the increased IL-13 production in EP2鈭?鈭?/sup> mice was due to the lack of EP2 specifically on T cells. Adoptive transfer of CD4+ EP2鈭?鈭?/sup> T cells caused greater cytokine production in the lungs of WT mice than did transfer of WT CD4+ T cells.}

Conclusion

We conclude that the PGE₂-EP2 axis is an important endogenous brake on allergic airway inflammation and primarily targets T cells and that its agonism represents a potential novel therapeutic approach to asthma.