Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
J Pharmacol Exp Ther. 2010 Sep 1;334(3):964-72. doi: 10.1124/jpet.110.169102. Epub 2010 Jun 17.
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-gamma and tumor necrosis factor alpha, 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.
移植后糖尿病是移植受者常见的并发症。晚期糖基化终产物（AGEs）与其在单核细胞/巨噬细胞上的受体结合在糖尿病并发症中起作用。单核细胞/巨噬细胞上粘附分子表达的增强激活 T 细胞，从而降低移植物的存活率。在以前的工作中，我们发现有毒的 AGEs，AGE-2 和 AGE-3，诱导单核细胞上细胞间粘附分子-1、B7.1、B7.2 和 CD40 的表达，产生干扰素-γ和肿瘤坏死因子-α，并在人混合淋巴细胞反应中促进淋巴细胞增殖。AGE 诱导的粘附分子表达上调参与细胞因子产生和淋巴细胞增殖。前列腺素 E2（PGE2）浓度依赖性地抑制 AGE-2 和 AGE-3 的作用。PGE2 的作用被 EP2 受体激动剂，ONO-AE1-259-01（11,15-O-二甲基 PGE2）和 EP4 受体激动剂，ONO-AE1-329[16-（3-甲氧基甲基）苯基-ω-四氢-3,7-二硫杂 PGE1]模拟。EP2 受体拮抗剂，AH6809（6-异丙氧基-9-氧杂蒽-2-羧酸）和 EP4 受体拮抗剂，AH23848[（4Z）-7-[(rel-1S,2S,5R)-5-（（1,1'-联苯-4-基）甲氧基）-2-（4-吗啉基）-3-氧代环戊基]-4-庚烯酸]，抑制 PGE2 的作用。据报道，EP2 和 EP4 受体的刺激会增加 cAMP 水平。PGE2 的作用被蛋白激酶 A（PKA）抑制剂逆转，并被二丁酰 cAMP 和腺苷酸环化酶激活剂， forskolin 模拟。这些结果表明，PGE2 通过 EP2/EP4 受体和 cAMP/PKA 途径抑制 AGE-2 和 AGE-3 的作用。
