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-γ and tumor necrosis factor α, 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.
Footnotes
This work was supported in part by the Japan Society for the Promotion of Science [Grants 18590509, 20590539, 17659159, 19659061, 21659141, 21390071, 215905694]; the Scientific Research from Ministry of Health, Labor, and Welfare of Japan; and the Takeda Science Foundation.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.169102.
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ABBREVIATIONS:
- DM
- diabetes mellitus
- PTDM
- posttransplant diabetes mellitus
- AGE
- advanced glycation end product
- BSA
- bovine serum albumin
- COX
- cyclooxygenase
- CsA
- cyclosporine A
- dbcAMP
- dibutyryl cAMP
- ELISA
- enzyme-linked immunosorbent assay
- ICAM
- intercellular adhesion molecule
- IFN
- interferon
- IL
- interleukin
- LPS
- lipopolysaccharide
- MLR
- mixed lymphocyte reaction
- PBMC
- peripheral blood mononuclear cell
- PGE2
- prostaglandin E2
- PKA
- protein kinase A
- PKI
- protein kinase inhibitor
- RAGE
- receptor for advanced glycation end products
- sRAGE
- soluble RAGE
- TNF
- tumor necrosis factor
- ONO-DI-004
- 17S-2,5-ethano-6-oxo-17,20-dimethyl prostaglandin E1
- ONO-AE1-259-01
- 11,15-O-dimethyl prostaglandin E2
- ONO-AE-248
- 16S-9-deoxy-9β-chloro-15-deoxy-16-hyfroxy-17,17-trimethylene-19,20-didehydro prostaglandin F2
- ONO-AE1-329
- 16-(3-methoxymethyl)phenyl-omega-tetranor-3,7dithia prostaglandin E1
- AH6809
- 6-isopropoxy-9-oxaxanthene-2-carboxylic acid
- AH23848
- (4Z)-7-[(rel-1S,2S,5R)-5-((1,1′-biphenyl-4-yl)methoxy)-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid
- H-89
- N-[2-(p-bromocinnamyl-amino)ethyl]-5-isoquinolinesulfonamide dihydrochloride)
- PKI
- protein kinase inhibitor
- KT5720
- (9S,10S,12R)-2,3,9,10,12-hexahydro-10-hydroxy-9-methyl-1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg: 3′,2′,1′-kl]pyrrolo[3,4-i][1,6]-benzo-diazocine-10-carboxylic acid hexyl ester.
- Received April 7, 2010.
- Accepted June 11, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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