Prostaglandin E receptor subtype EP3 in conjunctival epithelium regulates late-phase reaction of experimental allergic conjunctivitis Mayumi Ueta, MD,

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Prostaglandin E receptor subtype EP3 in conjunctival epithelium regulates late-phase reaction of experimental allergic conjunctivitis Mayumi Ueta, MD, PhD, Toshiyuki Matsuoka, MD, PhD, Shuh Narumiya, MD, PhD, Shigeru Kinoshita, MD, PhD Journal of Allergy and Clinical Immunology Volume 123, Issue 2, Pages 466-471.e5 (February 2009) DOI: 10.1016/j.jaci.2008.09.044 Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Expression and localization of EP3 in the conjunctiva and cornea. A, RT-PCR analyses of the expression of EP3-specific mRNA in the cornea and conjunctiva of wild-type mice. B, Histochemical staining for EP3 (X-gal): wild-type mice (a) and Ptger3−/− mice (b-d). Data are representative of 3 experiments. C, Immunohistologic analysis for EP3. Each bar represents a length of 500 (B, a, b), 50 (B, c, d), or 100 (C) μm. Data are representative of 3 experiments. ∗Conjunctival epithelium, #corneal epithelium, ∋Corneal endothelium. Journal of Allergy and Clinical Immunology 2009 123, 466-471.e5DOI: (10.1016/j.jaci.2008.09.044) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Histologic analyses of eosinophil inflammation in conjunctiva. Infiltration of eosinophils into the conjunctiva of wild-type and Ptger3−/− mice were detected by using the Luna method, which stained eosinophil granules with a distinctive red. Scale bars = 50 μm. Journal of Allergy and Clinical Immunology 2009 123, 466-471.e5DOI: (10.1016/j.jaci.2008.09.044) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Real-time PCR analyses of the expression of eotaxin-1 mRNA in the eyelids 6 hours after RW challenge. Relative mRNA expression levels for eotaxin-1 normalized by GAPDH are shown. Data are shown as the mean ± SEM of 7 samples per group. ∗P < .05. Journal of Allergy and Clinical Immunology 2009 123, 466-471.e5DOI: (10.1016/j.jaci.2008.09.044) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 RW challenge increased PGE2 synthesis in eyelids. A, Time course of COX-2 and mPGES-1 mRNA expression in eyelids during EAC. The y-axis shows the increase of specific mRNA over that seen in 0-hour samples. The x-axis shows the time after the RW challenge. Data are shown as the mean ± SEM of 3 samples. B, Time course of PGE2 content in eyelids during EAC. The x-axis shows the time after the RW challenge. Data are shown as the mean ± SEM of 4 samples. C, Localization of mPGES-1 on the ocular surface. Each bar represents a length of 100 μm. Journal of Allergy and Clinical Immunology 2009 123, 466-471.e5DOI: (10.1016/j.jaci.2008.09.044) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 The effects of an EP3-selective agonist on eosinophil infiltration in conjunctiva. Data are shown as the mean ± SEM of samples from all the mice examined. Negative control (RW sensitization without challenge), positive control (RW sensitization with challenge) only vehicle, and AE248 are shown. (Wild-type mice: negative control, n = 20; positive control, n = 20; vehicle only, n = 25; AE248, n = 30; Ptger3−/− mice: negative control, n = 11; positive control, n = 11; vehicle only, n = 14; AE248, n = 16). ∗∗∗∗∗P < .0005. Journal of Allergy and Clinical Immunology 2009 123, 466-471.e5DOI: (10.1016/j.jaci.2008.09.044) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Antibody responses to RW sensitization and challenge Antibody responses to RW sensitization and challenge. The serum concentration of total IgE (left) and the log titer of RW-specific IgE (middle) and RW-specific IgG1 (right) assessed by means of ELISA are shown. Sera were prepared from sensitized wild-type and Ptger3−/− mice at 24 hours after RW challenge. Sera from unsensitized wild-type mice were used as controls. Data are shown as the means ± SEMs of 8 samples. Journal of Allergy and Clinical Immunology 2009 123, 466-471.e5DOI: (10.1016/j.jaci.2008.09.044) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

The optimal dose of ONO-AE-248 The optimal dose of ONO-AE-248. ONO-AE-248 was administered at various doses (0.01 ng, 0.1, 1, 10, 100 ng) in 5 μL of PBS per eye to wild-type mice at 1, 3, and 7 hours after RW challenge. The quantified eosinophil numbers in conjunctivas of wild-type mice were shown. The data from the mice without both RW challenge and topical treatment and the mice without topical treatment were used as negative and positive controls, respectively. Data are shown as the means ± SEMs of samples from all mice examined. Positive control (RW sensitization with challenge), n = 19; negative control (RW sensitization without challenge), n = 19. AE248: 0.01 ng, n = 18; 0.1 ng, n = 6; 1 ng, n = 27; 10 ng, n = 6; 100 ng, n = 17. Journal of Allergy and Clinical Immunology 2009 123, 466-471.e5DOI: (10.1016/j.jaci.2008.09.044) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Infiltration of eosinophils into the conjunctiva treated with an EP3-selective agonist. Infiltrations of eosinophils were detected by using the Luna method, which stained eosinophil granules with a distinctive red. Scale bars = 50 μm. Journal of Allergy and Clinical Immunology 2009 123, 466-471.e5DOI: (10.1016/j.jaci.2008.09.044) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions

The expression of EP3 in human conjunctival epithelium The expression of EP3 in human conjunctival epithelium. A, RT-PCR analyses of the expression of EP3-specific mRNA. GAPDH, Glyceraldehyde-3-phosphate dehydrogenase. B, Immunohistologic analysis for EP3. Each bar represents a length of 50 μm. Journal of Allergy and Clinical Immunology 2009 123, 466-471.e5DOI: (10.1016/j.jaci.2008.09.044) Copyright © 2009 American Academy of Allergy, Asthma & Immunology Terms and Conditions