Prostaglandin E2 suppresses allergic sensitization and lung inflammation by targeting the E prostanoid 2 receptor on T cells Zbigniew Zasłona, PhD, Katsuhide.

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Prostaglandin E2 suppresses allergic sensitization and lung inflammation by targeting the E prostanoid 2 receptor on T cells Zbigniew Zasłona, PhD, Katsuhide Okunishi, MD, PhD, Emilie Bourdonnay, PhD, Racquel Domingo-Gonzalez, BS, Bethany B. Moore, PhD, Nicholas W. Lukacs, PhD, David M. Aronoff, MD, Marc Peters-Golden, MD Journal of Allergy and Clinical Immunology Volume 133, Issue 2, Pages 379-387.e1 (February 2014) DOI: 10.1016/j.jaci.2013.07.037 Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Enhanced allergic inflammation in EP2−/− animals. A, Schematic representation of the experimental protocol. B-D, EP2−/− mice have increased numbers of eosinophils and total cells in BALF after airway challenge. E, EP2−/− mice have increased cytokine levels in BALF after airway challenge (n = 4). F, EP2−/− mice have increased serum IgE levels. Samples were collected 24 hours after the second airway challenge (n = 3). *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2014 133, 379-387.e1DOI: (10.1016/j.jaci.2013.07.037) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Augmented TH2 responses in EP2−/− mice are present during the sensitization phase. A and B, Thoracic lymph node cells (Fig 2, A) and splenocytes (Fig 2, B) were isolated after the second airway challenge and cultured for 3 days in the presence of OVA. Controls were cultured without OVA (n = 4). C, Splenocytes isolated from mice after sensitization and without airway challenge were cultured for 3 days. Culture supernatants were analyzed for IL-13 by means of ELISA (n = 4). *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2014 133, 379-387.e1DOI: (10.1016/j.jaci.2013.07.037) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Exogenous PGE2 suppresses splenocyte IL-13 production through cAMP signaling. Splenocytes from sensitized WT and EP2−/− mice were cultured for 3 days with 10 μg/mL OVA in the presence of PGE2, EP2 agonist, EP3, EP4 agonist (all at 1 μmol/L), or the PKA-specific cAMP analog 6-Bnz-cAMP or the Epac-specific cAMP analog 8-pCPT-2′-O-Me-cAMP (both at 500 μmol/L). Treatments indicated with # were statistically different (P < .001) compared with control values. ***P < .001 (n = 4). Journal of Allergy and Clinical Immunology 2014 133, 379-387.e1DOI: (10.1016/j.jaci.2013.07.037) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Subcutaneous administration of a PGE2 analog during the sensitization phase inhibits allergic inflammation after airway challenge. A, Schematic representation of the misoprostol treatment protocol (50 μg of misoprostol or DMSO vehicle administered 2 hours before and 10 hours after sensitization). B and C, Misoprostol reduces eosinophilia in WT but not EP2−/− mice. D, Misoprostol reduces BALF IL-5 and IL-13 levels in WT but not EP2−/− mice. E, Misoprostol reduces serum IgE levels in WT but not EP2−/− mice. F, Splenocytes isolated from WT but not EP2−/− mice treated with misoprostol have decreased IL-13 production in vitro (n = 4). *P < .05 and **P < .01. Journal of Allergy and Clinical Immunology 2014 133, 379-387.e1DOI: (10.1016/j.jaci.2013.07.037) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 PGE2 inhibits IL-13 production primarily by inhibiting T cells through EP2. A, EP2 deficiency on T cells primarily contributes to enhanced TH2 responses in EP2−/− mice. Purified DCs and T cells were cocultured at a ratio of 1:10 for 3 days in the presence of 100 μg/mL OVA. Data are from 1 experiment that is representative of 3 independent experiments. B, CD4+ T cells from EP2−/− mice exhibited significantly higher IL-13 production than cells from WT mice. C, PGE2 suppresses TH2 polarization. Purified CD4+ T cells were cultured in the presence of 1 μmol/L PGE2, EP2, EP3, or EP4 agonist or 500 μmol/L PKA-specific cAMP analog 6-Bnz-cAMP or the Epac-specific cAMP analog 8-pCPT-2′-O-Me-cAMP. #Treatments statistically different compared with control values (n = 3). **P < .01 and ***P < .001. Journal of Allergy and Clinical Immunology 2014 133, 379-387.e1DOI: (10.1016/j.jaci.2013.07.037) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 PGE2 inhibits STAT6 phosphorylation (p-STAT6) in T cells. A, CD4 T cells cultured for 3 days in the presence of 1 μmol/L PGE2 exhibit decreased STAT6 phosphorylation on residue Y641. B, CD4 T cells pretreated for 30 minutes with 1 μmol/L PGE2 and subsequently treated for 5 minutes with recombinant IL-4 (25 ng/mL) have decreased STAT6 phosphorylation (n = 4). *P < .05. Journal of Allergy and Clinical Immunology 2014 133, 379-387.e1DOI: (10.1016/j.jaci.2013.07.037) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 Adoptive transfer of CD4+ T cells from EP2−/− mice induces increased cytokine production in WT mice. A, Schematic representation of the experimental protocol. i.v., Intravenous. B, Naive WT mice were injected intravenously with 5 × 106 purified CD4+ T cells from asthmatic WT or EP2−/− mice. Twenty-four hours later, mice were challenged with OVA, and BALF was collected 24 hours thereafter for cytokine determination by means of ELISA. WT values were set at 100% (n = 4). *P < .05. Journal of Allergy and Clinical Immunology 2014 133, 379-387.e1DOI: (10.1016/j.jaci.2013.07.037) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Subcutaneous administration of a PGE2 analog during the airway challenge phase inhibits allergic inflammation. A, Schematic representation of the misoprostol treatment protocol (50 μg of misoprostol or DMSO vehicle administered 2 hours before and 10 hours after airway challenge). i.p., Intraperitoneal; s.c., subcutaneous. B-F, Misoprostol reduces lung eosinophilia and TH2 cytokine levels in WT mice (n = 3). *P < .05. Journal of Allergy and Clinical Immunology 2014 133, 379-387.e1DOI: (10.1016/j.jaci.2013.07.037) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions