ono-ae-248 and Conjunctivitis--Allergic

We first investigated whether the prostaglandin (PG) E2-PGE receptor subtype EP3 axis regulates the development of murine experimental allergic conjunctivitis because it has been reported that this pathway negatively regulates allergic reactions in a murine allergic asthma model. We observed that EP3 is constitutively expressed in mice conjunctival epithelium. EP3 knockout mice demonstrated significantly increased eosinophil infiltration in conjunctiva after ragweed challenge compared with wild-type mice. Consistently, significantly higher expression of eotaxin-1 messenger RNA was observed in Ptger3-/- mice. Conversely, treatment of wild-type mice with an EP3-selective agonist significantly decreased eosinophil infiltration, which was blunted in Ptger3-/- mice. Expression of cyclooxygenase-2 and PGE synthases was upregulated and PGE2 content increased in the eyelids after ragweed challenge. These data suggest that PGE2 acts on EP3 in the conjunctival epithelium and downregulates the progression of experimental allergic conjunctivitis. We next examined and compared the expression of EP3 in human conjunctival epithelium in various ocular surface diseases. Human conjunctival epithelium expressed EP3-specific messenger RNA and EP3 protein. Although we could clearly find positive signals in the conjunctival epithelium from patients with noninflammatory ocular surface diseases such as conjunctivochalasis and pterygium, we could not find positive signals in that from those with inflammatory disorders such as Stevens-Johnson syndrome and ocular cicatricial pemphigoid. Likewise, expression of the PGE receptor subtype EP4 was clearly found in the conjunctival epithelium from patients with conjunctivochalasis and pterygium but not from patients with Stevens-Johnson syndrome and ocular cicatricial pemphigoid.

Topics: Animals; Chemokine CCL11; Conjunctiva; Conjunctivitis, Allergic; Cyclooxygenase 2; Dinoprostone; Eosinophils; Epithelium; Gene Expression Regulation; Mice; Mice, Knockout; Prostaglandin-Endoperoxide Synthases; Receptors, Prostaglandin E, EP3 Subtype; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

We previously demonstrated that the prostaglandin E(2) (PGE(2))-EP3 pathway negatively regulates allergic reactions in a murine allergic asthma model.. We investigated whether the PGE(2)-EP3 pathway also regulates the development of murine experimental allergic conjunctivitis (EAC).. The expression of EP3 was examined by means of RT-PCR and immunohistochemistry in wild-type mice, as well as by means of 5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside staining in mice deficient in EP3 (Ptger3(-/-) mice) carrying the beta-galactosidase gene at the EP3 gene locus. EAC was induced by immunization of mice with short ragweed pollen (RW), followed by challenge with eye drops of RW, and eosinophil infiltration and eotaxin-1 mRNA expression in the conjunctiva were examined. Mice were also treated with a topical application of an EP3-selective agonist during the elicitation phase. Quantitative RT-PCR was used to detect expression of COXs and prostaglandin E synthases, and ELISA was used to measure PGE(2) production in the eyelid.. EP3 was constitutively expressed in conjunctival epithelium on the ocular surface. Ptger3(-/-) mice demonstrated significantly increased eosinophil infiltration in conjunctiva after RW challenge compared with wild-type mice. Consistently, significantly higher expression of eotaxin-1 mRNA was observed in Ptger3(-/-) mice. Conversely, treatment of wild-type mice with an EP3-selective agonist resulted in a significant decrease in eosinophil infiltration, which was blunted in Ptger3(-/-) mice. Expression of COX-2 and prostaglandin E synthases was upregulated and PGE(2) content was increased in the eyelids after RW challenge.. These data suggest that PGE(2) acts on EP3 in conjunctival epithelium and downregulates the progression of EAC.

Topics: Ambrosia; Animals; beta-Galactosidase; Chemokine CCL11; Conjunctiva; Conjunctivitis, Allergic; Cyclooxygenase 1; Cyclooxygenase 2; Dinoprostone; Disease Models, Animal; Eosinophils; Epithelium; Glyceraldehyde-3-Phosphate Dehydrogenases; Intramolecular Oxidoreductases; Mice; Mice, Inbred BALB C; Mice, Knockout; Pollen; Prostaglandin-E Synthases; Receptors, Prostaglandin E; Receptors, Prostaglandin E, EP3 Subtype; Up-Regulation