title: E prostanoid 2 (EP2)/EP4-mediated suppression of antigen-specific human T-cell responses by prostaglandin E2.
abstract: Prostaglandin E2 (PGE2) is a lipid mediator that displays important immunomodulatory properties, such as polarization of cytokine production by T cells. Recent investigations have revealed that the effect of PGE2 on cytokine production is greatly influenced by external stimuli; however, it is unclear whether PGE2 plays a significant role in major histocompatibility complex-mediated antigen-specific T-cell responses via binding to one of four subtypes of E prostanoid (EP) receptor alone or in combination. In the present study, we sought to determine the effect of PGE2 on antigen-specific CD4+ T-cell responses in humans, especially in terms of receptor specificity. We used purified protein derivative (PPD) and Cry j 1 as T helper type 1 (Th1) and Th2-inducing antigens, respectively. We generated several different Cry j 1- and PPD-specific T-cell lines (TCLs). PGE2 significantly and dose-dependently inhibited the proliferation and subsequent production of interleukin-4 by Cry j 1-specific TCLs and of interferon-gamma by PPD-specific TCLs upon antigen stimulation. Administration of EP2 receptor agonist and EP4 receptor agonist suppressed these responses in an adenylate cyclase-dependent manner, while EP1 and EP3 receptor agonists did not. Messenger RNA for EP2, EP3 and EP4, but not EP1, receptors were detected in Cry j 1- and PPD-specific TCLs, and no differences in EP receptor expression were observed between them. Furthermore, PGE2 and EP2 receptor agonist significantly inhibited interleukin-5 and interferon-gamma production by peripheral blood mononuclear cells in response to Cry j 1 and PPD stimulation, respectively. These results suggest that PGE2 suppresses both Th1- and Th2-polarized antigen-specific human T-cell responses via a cAMP-dependent EP2/EP4-mediated pathway.
authors.affiliation: Department of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. mokano@cc.okayama-u.ac.jp
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Okano
authors.forename: Yuji
authors.initials: Y
authors.lastname: Sugata
authors.forename: Tazuko
authors.initials: T
authors.lastname: Fujiwara
authors.forename: Rie
authors.initials: R
authors.lastname: Matsumoto
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nishibori
authors.forename: Kenji
authors.initials: K
authors.lastname: Shimizu
authors.forename: Megumi
authors.initials: M
authors.lastname: Maeda
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Kimura
authors.forename: Shin
authors.initials: S
authors.lastname: Kariya
authors.forename: Hisashi
authors.initials: H
authors.lastname: Hattori
authors.forename: Minehiko
authors.initials: M
authors.lastname: Yokoyama
authors.forename: Kosuke
authors.initials: K
authors.lastname: Kino
authors.forename: Kazunori
authors.initials: K
authors.lastname: Nishizaki
mesh_terms: D000067956:Adenylyl Cyclase Inhibitors; D000293:Adolescent; D000328:Adult; D000485:Allergens / Q000276:immunology; D052179:Antigens, Plant; D049109:Cell Proliferation; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D015232:Dinoprostone / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology; D007111:Immunity, Cellular; D008297:Male; D008875:Middle Aged; D010940:Plant Proteins / Q000276:immunology; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000276:immunology*; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014373:Tuberculin / Q000276:immunology
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D000485:Allergens; D052179:Antigens, Plant; C065290:Cry j I protein, Cryptomeria japonica; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; C545644:PTGER2 protein, human; C545650:PTGER4 protein, human; D010940:Plant Proteins; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014373:Tuberculin; D015232:Dinoprostone