期刊
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 133, 期 2, 页码 379-+出版社
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2013.07.037
关键词
Asthma; allergic sensitization; prostaglandin E-2; CD4 T cells
资金
- Deutsche Forschungsgemeinschaft (German Research Foundation)
- American Lung Association
- American Heart Association
- National Institutes of Health [R01 HL94311, R01 HL58897, AI065543, AI032302, HD057176]
- [T32 AI007413]
Background: Endogenous prostanoids have been suggested to modulate sensitization during experimental allergic asthma, but the specific role of prostaglandin (PG) E-2 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 PGE(2) analog misoprostol was administered during sensitization in both genotypes. In 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(-/-) CD4 T cells was used to validate the importance of EP2 expression on T cells. Results: Compared with 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 misoprostol during sensitization inhibited allergic inflammation. PGE(2) 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(-/-) 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 CD4(+) EP2(-/-) 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 PGE(2)-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.
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