Prostaglandin E2 Inhibits Advanced Glycation End Product-Induced Adhesion Molecule Expression, Cytokine Production, and Lymphocyte Proliferation in Human Peripheral Blood Mononuclear Cells
Prostaglandin E2 Inhibits Advanced Glycation End Product-Induced Adhesion Molecule Expression, Cytokine Production, and Lymphocyte Proliferation in Human Peripheral Blood Mononuclear Cells
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DOI：
10.1124/jpet.109.157594
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发表时间：
2009-11
影响因子：
3.5
通讯作者：
Hideo Takahashi;Keyue Liu;H. Wake;S. Mori;Jiyong Zhang;Rui Liu;T. Yoshino;M. Nishibori
中科院分区：
文献类型：
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作者：
Hideo Takahashi;Keyue Liu;H. Wake;S. Mori;Jiyong Zhang;Rui Liu;T. Yoshino;M. Nishibori
晚期糖基化终产物（AGE）亚型，暴露于糖后发生糖基化的蛋白质或脂质，可诱发糖尿病并发症。在各种AGE亚型中，甘油醛衍生的AGE （AGE-2）和乙醇醛衍生的AGE （AGE-3）已被证明在糖尿病患者的炎症中起作用。AGEs和AGEs受体的结合激活了单核细胞。由于细胞间粘附分子-1 （ICAM-1）、B7.1、B7.2和CD40与单核细胞及其配体在T细胞上的结合在细胞因子的产生中起作用，我们研究了AGE-2和AGE-3对单核细胞中ICAM-1、B7.1、B7.2和CD40的表达、干扰素γ和肿瘤坏死因子α的产生以及人外周血单核细胞中淋巴细胞增殖的影响以及前列腺素E2 （PGE2）对它们的调节作用。AGE-2和AGE-3诱导粘附分子的表达、细胞因子的产生和淋巴细胞的增殖。PGE2浓度依赖性地抑制了AGE-2和AGE-3的作用。ep2受体激动剂11,15- o -二甲基前列腺素E2 （ono - ae1 - 251 -01）和EP4受体激动剂16-（3-甲氧基甲基）苯基ω-四氨基-3,7-二甲基前列腺素E1 （ONO-AE1-329）模拟了PGE2的作用。ep2受体拮抗剂6-异丙氧基-9-氧杂蒽-2-羧酸（AH6809）和ep4受体拮抗剂(4Z)-7-[（rels - 1s,2S,5R)-5-（1,1 ' -联苯-4-基）甲氧基）-2-(4-morpholinyl)-3-氧环戊基]-4-庚酸（AH23848）抑制PGE2的作用。据报道，刺激EP2和EP4受体可增加cAMP水平。PGE2的作用被蛋白激酶a （PKA）抑制剂H89逆转，并被二丁基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途径抑制了AGE-2和AGE-3的作用。
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 E1 (ONO-AE1-329). An EP2-receptor antagonist, 6-isopropoxy-9-oxaxanthene-2-carboxylic acid (AH6809), and an EP4-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.