Mechanisms of allergy/immunology
Prostaglandin E2 suppresses human group 2 innate lymphoid cell function

https://doi.org/10.1016/j.jaci.2017.09.050Get rights and content
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Background

Group 2 innate lymphoid cells (ILC2s) are involved in the initial phase of type 2 inflammation and can amplify allergic immune responses by orchestrating other type 2 immune cells. Prostaglandin (PG) E2 is a bioactive lipid that plays protective roles in the lung, particularly during allergic inflammation.

Objective

We set out to investigate how PGE2 regulates human ILC2 function.

Methods

The effects of PGE2 on human ILC2 proliferation and intracellular cytokine and transcription factor expression were assessed by means of flow cytometry. Cytokine production was measured by using ELISA, and real-time quantitative PCR was performed to detect PGE2 receptor expression.

Results

PGE2 inhibited GATA-3 expression, as well as production of the type 2 cytokines IL-5 and IL-13, from human tonsillar and blood ILC2s in response to stimulation with a combination of IL-25, IL-33, thymic stromal lymphopoietin, and IL-2. Furthermore, PGE2 downregulated the expression of IL-2 receptor α (CD25). In line with this observation, PGE2 decreased ILC2 proliferation. These effects were mediated by the combined action of E-type prostanoid receptor (EP) 2 and EP4 receptors, which were specifically expressed on ILC2s.

Conclusion

Our findings reveal that PGE2 limits ILC2 activation and propose that selective EP2 and EP4 receptor agonists might serve as a promising therapeutic approach in treating allergic diseases by suppressing ILC2 function.

Key words

ILC2
allergy
prostaglandin E2
E-type prostanoid receptor 2
E-type prostanoid receptor 4

Abbreviations used

cAMP
Cyclic AMP
CRTH2
Chemoattractant receptor-homologous molecule expressed on TH2 cells
EP
E-type prostanoid receptor
ILC
Innate lymphoid cell
ILC2
Group 2 innate lymphoid cell
IMDM
Iscove modified Eagle medium
NHS
Normal human serum
NK
Natural killer
PE
Phycoerythrin
PG
Prostaglandin
RNA-seq
RNA sequencing
RT-qPCR
Quantitative RT-PCR
TSLP
Thymic stromal lymphopoietin

Cited by (0)

Supported by the Swedish Research Council (521-2013-2791), the Swedish Cancer Society (130396), the Foundation for Strategic Research (ICA12-0023), and the Swedish Society for Medical Research (to J.M.) and the Austrian Science Fund FWF (grant P25531-B23; to V.K.).

Disclosure of potential conflict of interest: S.-E. Dahlen has received grants from the Swedish Research Council (521-2013-2791), the Swedish Cancer Society (130396), the Foundation for Strategic Research (ICA12-0023), and AstraZeneca; has a board membership with RSPR Pharma AB; and has consultant arrangements with AstraZeneca, GlaxoSmithKline, Merck, Novartis, Regeneron/Sanofi, RSPR Pharma AB, and Teva. A. Heinemann has received consultant arrangements AstraZeneca, Bayer, and Amgen; has received grants from Austrian Science Funds; and has received payment for lectures from Eli Lilly. V. Konya has received a grant from the Austrian Science Fund (FWF). J. Mjösberg has received grants from the Swedish Research Council, the Swedish Cancer Foundation, the Knut and Alice Wallenberg Foundation, the Swedish Foundation for Strategic Research, and the Swedish Society for Medical Research. The rest of the authors declare that they have no relevant conflicts of interest.

These authors contributed equally to this work.