E prostanoid 2 (EP2)/EP4-mediated suppression of antigen-specific human T-cell responses by prostaglandin E2
E prostanoid 2 (EP2)/EP4-mediated suppression of antigen-specific human T-cell responses by prostaglandin E2
复制标题
DOI：
10.1111/j.1365-2567.2006.02376.x
复制
发表时间：
2006-07-01
期刊：
影响因子：
6.4
通讯作者：
Nishizaki, Kazunori
中科院分区：
文献类型：
--
作者：
Okano, Mitsuhiro;Sugata, Yuji;Nishizaki, Kazunori
前列腺素 E-2 (PGE(2)) 是一种脂质介质，具有重要的免疫调节特性，例如 T 细胞产生细胞因子的极化。最近的研究表明，PGE(2)对细胞因子产生的影响很大程度上受外界刺激的影响。然而，尚不清楚 PGE(2) 是否通过单独或组合与 E 前列腺素 (EP) 受体四种亚型之一结合，在主要组织相容性复合物介导的抗原特异性 T 细胞反应中发挥重要作用。在本研究中，我们试图确定 PGE(2) 对人类抗原特异性 CD4(+) T 细胞反应的影响，特别是在受体特异性方面。我们使用纯化蛋白衍生物 (PPD) 和 Cry j 1 分别作为 1 型辅助 T (Th1) 和 Th2 诱导抗原。我们生成了几种不同的 Cry j 1 和 PPD 特异性 T 细胞系 (TCL)。在抗原刺激后，PGE(2) 显着且剂量依赖性地抑制 Cry j 1 特异性 TCL 产生的白细胞介素 4 的增殖和随后产生，以及 PPD 特异性 TCL 产生的干扰素 γ 的增殖和随后产生。给予 EP2 受体激动剂和 EP4 受体激动剂以腺苷酸环化酶依赖性方式抑制这些反应，而 EP1 和 EP3 受体激动剂则不然。在 Cry j 1 和 PPD 特异性 TCL 中检测到 EP2、EP3 和 EP4 受体的信使 RNA，但未检测到 EP1 受体，并且在它们之间没有观察到 EP 受体表达的差异。此外，PGE(2) 和 EP2 受体激动剂分别显着抑制外周血单核细胞响应 Cry j 1 和 PPD 刺激而产生白细胞介素 5 和干扰素 γ。这些结果表明，PGE(2) 通过 cAMP 依赖性 EP2/EP4 介导的途径抑制 Th1 和 Th2 极化的抗原特异性人类 T 细胞反应。
Prostaglandin E-2 (PGE(2)) is a lipid mediator that displays important immunomodulatory properties, such as polarization of cytokine production by T cells. Recent investigations have revealed that the effect of PGE(2) on cytokine production is greatly influenced by external stimuli; however, it is unclear whether PGE(2) plays a significant role in major histocompatibility complex-mediated antigen-specific T-cell responses via binding to one of four subtypes of E prostanoid (EP) receptor alone or in combination. In the present study, we sought to determine the effect of PGE(2) on antigen-specific CD4(+) T-cell responses in humans, especially in terms of receptor specificity. We used purified protein derivative (PPD) and Cry j 1 as T helper type 1 (Th1) and Th2-inducing antigens, respectively. We generated several different Cry j 1- and PPD-specific T-cell lines (TCLs). PGE(2) significantly and dose-dependently inhibited the proliferation and subsequent production of interleukin-4 by Cry j 1-specific TCLs and of interferon-gamma by PPD-specific TCLs upon antigen stimulation. Administration of EP2 receptor agonist and EP4 receptor agonist suppressed these responses in an adenylate cyclase-dependent manner, while EP1 and EP3 receptor agonists did not. Messenger RNA for EP2, EP3 and EP4, but not EP1, receptors were detected in Cry j 1- and PPD-specific TCLs, and no differences in EP receptor expression were observed between them. Furthermore, PGE(2) and EP2 receptor agonist significantly inhibited interleukin-5 and interferon-gamma production by peripheral blood mononuclear cells in response to Cry j 1 and PPD stimulation, respectively. These results suggest that PGE(2) suppresses both Th1- and Th2-polarized antigen-specific human T-cell responses via a cAMP-dependent EP2/EP4-mediated pathway.