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.
|Number of pages||15|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|Publication status||Published - Nov 2009|
ASJC Scopus subject areas
- Molecular Medicine