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阿司匹林引发的脂氧素A4和B4类似物可阻断人T细胞中细胞外信号调节激酶依赖性肿瘤坏死因子-α的分泌。

Aspirin-triggered lipoxin A4 and B4 analogs block extracellular signal-regulated kinase-dependent TNF-alpha secretion from human T cells.

作者信息

Ariel Amiram, Chiang Nan, Arita Makoto, Petasis Nicos A, Serhan Charles N

机构信息

Department of Anesthesiology, Perioperative and Pain Medicine, Center for Experimental Therapeutics and Reperfusion Injury, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.

出版信息

J Immunol. 2003 Jun 15;170(12):6266-72. doi: 10.4049/jimmunol.170.12.6266.

Abstract

Lipoxins (LX) and their aspirin-triggered 15-epimer endogenous isoforms are endogenous anti-inflammatory and pro-resolution eicosanoids. In this study, we examined the impact of LX and aspirin-triggered LXA(4)-stable analogs (ATLa) on human T cell functions. 15-epi-16-(p-fluoro)phenoxy-LXA(4) (ATLa(1)) blocked the secretion of TNF-alpha from human PBMC after stimulation by anti-CD3 Abs, with the IC(50) value of approximately 0.05 nM. A similar action was also exerted by the native aspirin-triggered 15-epi-LXA(4), a new 15-epi-16-(p-trifluoro)phenoxy-LXA(4) analog (ATLa(2)), as well as LXB(4), and its analog 5-(R/S)-methyl-LXB(4). The LXA(4) receptor (ALX) is expressed in peripheral blood T cells and mediates the inhibition of TNF-alpha secretion from activated T cells by ATLa(1). This action was accomplished by inhibition of the anti-CD3-induced activation of extracellular signal-regulated kinase, which is essential for TNF-alpha secretion from anti-CD3-activated T cells. These results demonstrate novel roles for LX and aspirin-triggered LX in the regulation of T cell-mediated responses relevant in inflammation and its resolution. Moreover, they provide potential counterregulatory signals in communication(s) between the innate and acquired immune systems.

摘要

脂氧素(LX)及其阿司匹林触发的15-表位内源性异构体是内源性抗炎和促炎症消退的类二十烷酸。在本研究中,我们检测了LX和阿司匹林触发的LXA4稳定类似物(ATLa)对人T细胞功能的影响。15-表位-16-(对氟)苯氧基-LXA4(ATLa1)在抗CD3抗体刺激后可阻断人外周血单个核细胞(PBMC)分泌肿瘤坏死因子-α(TNF-α),半数抑制浓度(IC50)值约为0.05 nM。天然的阿司匹林触发的15-表位-LXA4、一种新的15-表位-16-(对三氟)苯氧基-LXA4类似物(ATLa2)、以及LXB4及其类似物5-(R/S)-甲基-LXB4也有类似作用。LXA4受体(ALX)在外周血T细胞中表达,并介导ATLa1对活化T细胞分泌TNF-α的抑制作用。该作用是通过抑制抗CD3诱导的细胞外信号调节激酶的激活来实现的,而细胞外信号调节激酶的激活对于抗CD3激活的T细胞分泌TNF-α至关重要。这些结果证明了LX和阿司匹林触发的LX在调节与炎症及其消退相关的T细胞介导反应中的新作用。此外,它们在先天免疫系统和获得性免疫系统之间的通讯中提供了潜在的反向调节信号。

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