Prostaglandin E2 inhibits advanced glycation end product-induced adhesion molecule expression on monocytes, cytokine production, and lymphocyte proliferation during human mixed lymphocyte reaction

Hideo Kohka Takahashi, Jiyong Zhang, Shuji Mori, Keyue Liu, Hidenori Wake, Rui Liu, Hiroshi Sadamori, Hiroaki Matsuda, Takahito Yagi, Tadashi Yoshino, Masahiro Nishibori

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)964-972
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume334
Issue number3
DOIs
Publication statusPublished - 2010

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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