Prostaglandin E₂ inhibits advanced glycation end product-induced adhesion molecule expression, cytokine production, and lymphocyte proliferation in human peripheral blood mononuclear cells

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 γ and tumor necrosis factor α, and the lymphocyte proliferation in human peripheral blood mononuclear cells and their modulation by prostaglandin E₂ (PGE₂). AGE-2 and AGE-3 induced the expressions of adhesion molecule, the cytokine production, and the lymphocyte proliferation. PGE₂ concentration-dependently inhibited the actions of AGE-2 and AGE-3. The effects of PGE₂ were mimicked by an E-prostanoid (EP)₂-receptor agonist, 11,15-O-dimethyl prostaglandin E₂ (ONO-AE1-259-01), and an EP₄ receptor agonist, 16-(3-methoxymethyl)phenyl-ω-tetranor-3,7-dithia prostaglandin E ₁ (ONO-AE1-329). An EP₂-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 PGE₂. The stimulation of EP₂ and EP₄ receptors is reported to increase cAMP levels. The effects of PGE₂ 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 PGE₂ inhibited the actions of AGE-2 and AGE-3 via EP₂/EP₄ receptors and the cAMP/PKA pathway.