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      Prostaglandin E2 signal inhibits T regulatory cell differentiation during allergic rhinitis inflammation through EP4 receptor

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          Abstract

          Objective

          Allergic rhinitis (AR) is a common disease seriously affecting quality of life, and until now the effect of medical therapy is not satisfactory. It is essential to explore in depth the pathologic mechanism of AR to offer new ideas for developing novel treatment strategies. The defect of T regulatory (Treg) cells plays a critical role in the pathogenesis of AR, but the underlying mechanism remains to be elucidated. This study aims to determine the effect of Prostaglandin E2 (PGE2) on the differentiation of Treg cells in AR patients and the involvement of E prostanoid (EP) receptor signaling pathway.

          Methods

          The proportion of Treg cells and the level of PGE2 in the peripheral blood of AR patients and healthy controls were compared. Differentiation rate of Treg cells under the influence of various concentrations of PGE2 with or without diverse EP receptor agonists and antagonists were investigated through cell culture and flow cytometry in vitro. The cyclic AMP (cAMP) mimic or protein kinase B (Akt) inhibitor was also added to the culture to evaluate the downstream pathway of EP receptor signaling.

          Results

          The proportion of Treg cells decreased and PGE2 concentration increased in the peripheral blood of AR patients compared to healthy controls. PGE2 dose-dependently suppressed the differentiation of Treg cells from both human and mice naïve CD4 + T cells in vitro. This inhibitory effect was mediated through EP4 via a mechanism involving activation of cAMP-dependent proteinkinase A (PKA) signaling pathway.

          Conclusion

          PGE2-EP4-cAMP signaling might mediate the development of AR by inhibiting the differentiation of Treg cells.

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          Mechanisms of allergen immunotherapy for inhaled allergens and predictive biomarkers

          Mohamed Shamji, Stephen Durham (2017)
          Allergen immunotherapy is effective in patients with IgE-dependent allergic rhinitis and asthma. When immunotherapy is given continuously for 3 years, there is persistent clinical benefit for several years after its discontinuation. This disease-modifying effect is both antigen-specific and antigen-driven. Clinical improvement is accompanied by decreases in numbers of effector cells in target organs, including mast cells, basophils, eosinophils, and type 2 innate lymphoid cells. Immunotherapy results in the production of blocking IgG/IgG4 antibodies that can inhibit IgE-dependent activation mediated through both high-affinity IgE receptors (FcεRI) on mast cells and basophils and low-affinity IgE receptors (FcεRII) on B cells. Suppression of TH2 immunity can occur as a consequence of either deletion or anergy of antigen-specific T cells; induction of antigen-specific regulatory T cells; or immune deviation in favor of TH1 responses. It is not clear whether the altered long-term memory resides within the T-cell or the B-cell compartment. Recent data highlight the role of IL-10-producing regulatory B cells and "protective" antibodies that likely contribute to long-term tolerance. Understanding mechanisms underlying induction and persistence of tolerance should identify predictive biomarkers of clinical response and discover novel and more effective strategies for immunotherapy.
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            Tumor cyclooxygenase-2/prostaglandin E2-dependent promotion of FOXP3 expression and CD4+ CD25+ T regulatory cell activities in lung cancer.

            Sherven Sharma, Byoung-Chul Yang, B Gardner … (2005)
            Cyclooxygenase (COX)-2 and its product prostaglandin (PG) E2 underlie an immunosuppressive network that is important in the pathogenesis of non-small cell lung cancer. CD4+ CD25+ T regulatory (Treg) cells play an important role in maintenance of immunologic self-tolerance. CD4+ CD25+ Treg cell activities increase in lung cancer and appear to play a role in suppressing antitumor immune responses. Definition of the pathways controlling Treg cell activities will enhance our understanding of limitation of the host antitumor immune responses. Tumor-derived COX-2/PGE2 induced expression of the Treg cell-specific transcription factor, Foxp3, and increased Treg cell activity. Assessment of E-prostanoid (EP) receptor requirements revealed that PGE2-mediated induction of Treg cell Foxp3 gene expression was significantly reduced in the absence of the EP4 receptor and ablated in the absence of the EP2 receptor expression. In vivo, COX-2 inhibition reduced Treg cell frequency and activity, attenuated Foxp3 expression in tumor-infiltrating lymphocytes, and decreased tumor burden. Transfer of Treg cells or administration of PGE2 to mice receiving COX-2 inhibitors reversed these effects. We conclude that inhibition of COX-2/PGE2 suppresses Treg cell activity and enhances antitumor responses.
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              Prostaglandin E2 regulates Th17 cell differentiation and function through cyclic AMP and EP2/EP4 receptor signaling

              Katia Boniface, Kristian S. Bak-Jensen, Ying Li … (2009)
              Prostaglandins, particularly prostaglandin E2 (PGE2), play an important role during inflammation. This is exemplified by the clinical use of cyclooxygenase 2 inhibitors, which interfere with PGE2 synthesis, as effective antiinflammatory drugs. Here, we show that PGE2 directly promotes differentiation and proinflammatory functions of human and murine IL-17–producing T helper (Th17) cells. In human purified naive T cells, PGE2 acts via prostaglandin receptor EP2- and EP4-mediated signaling and cyclic AMP pathways to up-regulate IL-23 and IL-1 receptor expression. Furthermore, PGE2 synergizes with IL-1β and IL-23 to drive retinoic acid receptor–related orphan receptor (ROR)-γt, IL-17, IL-17F, CCL20, and CCR6 expression, which is consistent with the reported Th17 phenotype. While enhancing Th17 cytokine expression mainly through EP2, PGE2 differentially regulates interferon (IFN)-γ production and inhibits production of the antiinflammatory cytokine IL-10 in Th17 cells predominantly through EP4. Furthermore, PGE2 is required for IL-17 production in the presence of antigen-presenting cells. Hence, the combination of inflammatory cytokines and noncytokine immunomodulators, such as PGE2, during differentiation and activation determines the ultimate phenotype of Th17 cells. These findings, together with the altered IL-12/IL-23 balance induced by PGE2 in dendritic cells, further highlight the crucial role of the inflammatory microenvironment in Th17 cell development and regulation.
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                Author and article information

                Contributors
                Wei Wang
                Journal
                Journal ID (nlm-ta): World Allergy Organ J
                Journal ID (iso-abbrev): World Allergy Organ J
                Title: The World Allergy Organization Journal
                Publisher: World Allergy Organization
                ISSN (Electronic): 1939-4551
                Publication date PMC-release: 29 November 2019
                Publication date Collection: December 2019
                Publication date (Electronic): 29 November 2019
                Volume: 12
                Issue: 12
                Electronic Location Identifier: 100090
                Affiliations
                [a ]Department of Allergy, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing Key Laboratory of Precision Medicine for Diagnosis and Treatment on Allergic Diseases, National Clinical Research Center for Immunologic Diseases, Beijing, 100730, China
                [b ]Department of Immunology, School of Basic Medical Sciences, Peking University, NHC Key Laboratory of Medical Immunology (Peking University), Key Laboratory of Molecular Immunology, Chinese Academy of Medical Sciences, Beijing, 100191, China
                Author notes
                [∗ ]Corresponding author. wangwei83427@ 123456bjmu.edu.cn
                Article
                Publisher ID: S1939-4551(19)31246-3 Publisher ID: 100090
                DOI: 10.1016/j.waojou.2019.100090
                PMC ID: 6909350
                SO-VID: 737e5108-fd0f-4de9-8000-0fc4d4f860ad
                Copyright © © 2019 The Author(s)
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 8 May 2019
                Date revision received : 1 October 2019
                Date accepted : 17 October 2019
                Categories
                Subject: Article

                ScienceOpen disciplines: Immunology
                Keywords: allergic rhinitis,t regulatory cell,prostaglandin e2,ep receptor,signaling pathway
                Data availability:
                ScienceOpen disciplines: Immunology
                Keywords: allergic rhinitis, t regulatory cell, prostaglandin e2, ep receptor, signaling pathway

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