title: Prostaglandin E2 inhibits advanced glycation end product-induced adhesion molecule expression on monocytes, cytokine production, and lymphocyte proliferation during human mixed lymphocyte reaction.
abstract: Posttransplant diabetes mellitus is a frequent complication among transplant recipients. Ligation of advanced glycation end products (AGEs) with their receptor on monocytes/macrophages plays a role in diabetes complications. The enhancement of adhesion molecule expression on monocytes/macrophages activates T cells, reducing allograft survival. In previous work, we found that toxic AGEs, AGE-2 and AGE-3, induced the expression of intracellular adhesion molecule-1, B7.1, B7.2, and CD40 on monocytes, production of interferon-gamma and tumor necrosis factor alpha, and lymphocyte proliferation during human mixed lymphocyte reaction. AGE-induced up-regulation of adhesion molecule expression was involved in cytokine production and lymphocyte proliferation. Prostaglandin E2 (PGE2) concentration-dependently inhibited the actions of AGE-2 and AGE-3. The effects of PGE2 were mimicked by an EP2 receptor agonist, ONO-AE1-259-01 (11,15-O-dimethyl PGE2), and an EP4 receptor agonist, ONO-AE1-329 [16-(3-methoxymethyl)phenyl-omega-tetranor-3,7dithia PGE1]. An EP2 receptor antagonist, AH6809 (6-isopropoxy-9-oxaxanthene-2-carboxylic acid), and an EP4 receptor antagonist, AH23848 [(4Z)-7-[(rel-1S,2S,5R)-5-((1,1'-biphenyl-4-yl)methoxy)-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid], inhibited the actions of PGE2. The stimulation of EP2 and EP4 receptors is reported to increase cAMP levels. The effects of PGE2 were reversed by protein kinase A (PKA) inhibitors and mimicked by dibutyryl cAMP and an adenylate cyclase activator, forskolin. These results as a whole indicate that PGE2 inhibited the actions of AGE-2 and AGE-3 via EP2/EP4 receptors and the cAMP/PKA pathway.
authors.affiliation: Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan. kohka611@md.okayama-u.ac.jp
authors.forename: Hideo Kohka
authors.initials: HK
authors.lastname: Takahashi
authors.forename: Jiyong
authors.initials: J
authors.lastname: Zhang
authors.forename: Shuji
authors.initials: S
authors.lastname: Mori
authors.forename: Keyue
authors.initials: K
authors.lastname: Liu
authors.forename: Hidenori
authors.initials: H
authors.lastname: Wake
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sadamori
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Matsuda
authors.forename: Takahito
authors.initials: T
authors.lastname: Yagi
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yoshino
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nishibori
mesh_terms: D015815:Cell Adhesion Molecules / Q000096:biosynthesis*; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis*; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007959:Lymphocyte Culture Test, Mixed; D008214:Lymphocytes / Q000187:drug effects*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D018078:Receptors, Prostaglandin E / Q000819:agonists / Q000037:antagonists & inhibitors; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D015815:Cell Adhesion Molecules; D016207:Cytokines; D017127:Glycation End Products, Advanced; C545644:PTGER2 protein, human; C545650:PTGER4 protein, human; D047428:Protein Kinase Inhibitors; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D015232:Dinoprostone