E prostanoid 2 (EP2)/EP4-mediated suppression of antigen-specific human T-cell responses by prostaglandin E2.
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.
Okano
Mitsuhiro
M
Department of Otolaryngology-Head & Neck Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. mokano@cc.okayama-u.ac.jp
Sugata
Yuji
Y
Fujiwara
Tazuko
T
Matsumoto
Rie
R
Nishibori
Masahiro
M
Shimizu
Kenji
K
Maeda
Megumi
M
Kimura
Yoshinobu
Y
Kariya
Shin
S
Hattori
Hisashi
H
Yokoyama
Minehiko
M
Kino
Kosuke
K
Nishizaki
Kazunori
K
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
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