title: Prostaglandin E2 inhibits advanced glycation end product-induced adhesion molecule expression, cytokine production, and lymphocyte proliferation in human peripheral blood mononuclear cells.
abstract: Advanced glycation end product (AGE) subtypes, proteins or lipids that become glycated after exposure to sugars, induce complications in diabetes. Among the various AGE subtypes, glyceraldehyde-derived AGE (AGE-2) and glycolaldehyde-derived AGE (AGE-3) have been indicated to play roles in inflammation in diabetic patients. The engagement of AGEs and receptor for AGEs activates monocytes. Because the engagement of intercellular adhesion molecule-1 (ICAM-1), B7.1, B7.2, and CD40 on monocytes with their ligands on T cells plays roles in cytokine production, we investigated the effects of AGE-2 and AGE-3 on the expressions of ICAM-1, B7.1, B7.2, and CD40 on monocytes, the production of interferon gamma and tumor necrosis factor alpha, and the lymphocyte proliferation in human peripheral blood mononuclear cells and their modulation by prostaglandin E(2) (PGE(2)). AGE-2 and AGE-3 induced the expressions of adhesion molecule, the cytokine production, and the lymphocyte proliferation. PGE(2) concentration-dependently inhibited the actions of AGE-2 and AGE-3. The effects of PGE(2) were mimicked by an E-prostanoid (EP)(2)-receptor agonist, 11,15-O-dimethyl prostaglandin E(2) (ONO-AE1-259-01), and an EP(4) receptor agonist, 16-(3-methoxymethyl)phenyl-omega-tetranor-3,7-dithia prostaglandin E(1) (ONO-AE1-329). An EP(2)-receptor antagonist, 6-isopropoxy-9-oxaxanthene-2-carboxylic acid (AH6809), and an EP(4)-receptor antagonist, (4Z)-7-[(rel-1S,2S,5R)-5-(1,1'-biphenyl-4-yl)methoxy)-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid (AH23848), inhibited the actions of PGE(2). The stimulation of EP(2) and EP(4) receptors is reported to increase cAMP levels. The effects of PGE(2) were reversed by a protein kinase A (PKA) inhibitor, H89, and mimicked by a dibutyryl cAMP and an adenylate cyclase activator, forskolin. These results as a whole indicated that PGE(2) inhibited the actions of AGE-2 and AGE-3 via EP(2)/EP(4) receptors and the cAMP/PKA pathway.
authors.affiliation: Department of Pharmacology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan.
authors.forename: Hideo Kohka
authors.initials: HK
authors.lastname: Takahashi
authors.forename: Keyue
authors.initials: K
authors.lastname: Liu
authors.forename: Hidenori
authors.initials: H
authors.lastname: Wake
authors.forename: Shuji
authors.initials: S
authors.lastname: Mori
authors.forename: Jiyong
authors.initials: J
authors.lastname: Zhang
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yoshino
authors.forename: Masahiro
authors.initials: M
authors.lastname: Nishibori
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D003994:Bucladesine / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000096:biosynthesis*; D049109:Cell Proliferation / Q000187:drug effects; D002469:Cell Separation; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D016207:Cytokines / Q000096:biosynthesis*; D015232:Dinoprostone / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005434:Flow Cytometry; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors*; D006801:Humans; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects*; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000819:agonists; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D015815:Cell Adhesion Molecules; D016207:Cytokines; D017127:Glycation End Products, Advanced; D007546:Isoquinolines; C545644:PTGER2 protein, human; C545650:PTGER4 protein, human; D018078:Receptors, Prostaglandin E; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013449:Sulfonamides; D005576:Colforsin; D003994:Bucladesine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D000262:Adenylyl Cyclases; D015232:Dinoprostone; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide