Prostaglandin E₂ suppresses allergic sensitization and lung inflammation by targeting the E prostanoid 2 receptor on T cells.
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(-/-) 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 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. 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(-/-) 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.


CONCLUSIONS
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.
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Mich.
Zbigniew
Z
Zasłona
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Mich.
Katsuhide
K
Okunishi
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Mich.
Emilie
E
Bourdonnay
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Mich.
Racquel
R
Domingo-Gonzalez
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Mich.
Bethany B
BB
Moore
Department of Pathology, University of Michigan Medical School, Ann Arbor, Mich.
Nicholas W
NW
Lukacs
Division of Infectious Disease, University of Michigan Medical School, Ann Arbor, Mich.
David M
DM
Aronoff
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor, Mich. Electronic address: petersm@umich.edu.
Marc
M
Peters-Golden
D019264:Adoptive Transfer; D000485:Allergens; D000818:Animals; D001249:Asthma / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D015232:Dinoprostone / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016595:Misoprostol / Q000494:pharmacology; D010047:Ovalbumin; D011014:Pneumonia / Q000276:immunology*; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000276:immunology
D000485:Allergens; D016207:Cytokines; D058307:Receptors, Prostaglandin E, EP2 Subtype; D016595:Misoprostol; D010047:Ovalbumin; D015232:Dinoprostone
Asthma; BALF; Bronchoalveolar lavage fluid; CD4 T cells; Cyclic AMP; DC; DMSO; Dendritic cell; Dimethyl sulfoxide; E prostanoid; EP; Epac; Guanine nucleotide exchange protein directly activated by cAMP; NSAID; Nonsteroidal anti-inflammatory drug; OVA; Ovalbumin; PG; PKA; Prostaglandin; Protein kinase A; STAT; Signal transducer and activator of transcription; WT; Wild-type; allergic sensitization; cAMP; prostaglandin E(2)