A novel rat lipoxin A4 receptor that is conserved in structure and function
A novel rat lipoxin A4 receptor that is conserved in structure and function
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DOI：
10.1038/sj.bjp.0705220
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发表时间：
2003-05-01
影响因子：
7.3
通讯作者：
Serhan, CN
中科院分区：
文献类型：
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作者：
Chiang, N;Takano, T;Serhan, CN
1脂氧素(LX)A(4)和阿司匹林触发的LX(ATL)是内源性脂质衍生介质，通过特定的LXA(4)受体(ALX)调节白细胞的运输，参与内源性抗炎和分解。LXA(4)和ATL在体外和体内均由大鼠组织产生。在大鼠中，LXA(4)和ATL显示出强大的生理和病理生理学作用。因此，我们开始确定ALX是否在大鼠组织中表达，以及它在与LXA(4)和ATL一起调节白细胞运输方面的潜在作用。在大鼠中，一种稳定的ATL类似物，当连续静脉注射两次，每次约60ug kg(-1)时，显著抑制酪蛋白诱导的腹膜炎中的中性粒细胞渗透(类似于43%)和蛋白质外溢(类似于42%)。3大鼠ALX的同源基因是从编码一个可能的G蛋白偶联受体(GPCR)的外周白细胞中克隆出来的。与人和小鼠ALXA的氨基酸序列同源性分别为74%和84%。4核糖核酸酶保护的组织分布分析表明，LXA(4)在组织/细胞中表达，其中LXA(4)具有生理和病理生理作用，即肺、肾和白细胞。5大鼠ALX的同源基因与[H-3]LXA(4)和[(125)-Tyr]-Annexin 1衍生的多肽具有特异性的放射性配基结合，表观K-d值分别为5和820 nM。6利用荧光素酶报告基因系统，激活大鼠ALX以一种配体依赖的方式抑制肿瘤坏死因子α介导的核因子kappaB活性。7总之，这些结果首次证明了大鼠ALX在结构和功能上都是保守的，这表明ALX在调节从小鼠到人类物种的效应性免疫反应中发挥关键作用。
1 Lipoxin (LX) A(4) and aspirin-triggered- LX (ATL) are endogenous lipid-derived mediators that regulate leukocyte trafficking via specific LXA(4) receptors (ALX), and are involved in endogenous anti-inflammation and resolution. Both LXA(4) and ATL are produced by rat tissues in vitro as well as in vivo. In rats, LXA(4) and ATL exhibit potent physiological and pathophysiological roles. Thus, we set out to determine whether ALX is expressed in rat tissues and its potential role in modulating leukocyte trafficking with LXA(4) and ATL.2 In rats, a stable analog of ATL, when given intravenously with two consecutive doses at approximately 60 mug kg(-1) each injection, significantly inhibited neutrophil infiltration (similar to43%) and protein extravasation (similar to42%) in a casein-induced peritonitis.3 The rat orthologue of ALX was cloned from peripheral blood leukocytes encoding a putative G protein-coupled receptor (GPCR). It gave similar to74 and similar to84% homology, respectively to the deduced amino-acid sequences of the human and mouse ALX.4 Tissue distribution analysis by RNase protection revealed that this rat receptor is expressed in tissues/cells, where LXA(4) displays physiological and pathophysiological roles, namely, lung, kidney and leukocytes.5 The rat orthologue of ALX gave specific radioligand binding with [H-3]LXA(4) and [(125)-Tyr]-annexin 1-derived peptide with apparent K-d values of 5 and 820 nM, respectively, that are at levels comparable to those of the human ALX.6 Activation of rat ALX inhibited tumor necrosis factor alpha-mediated nuclear factor kappaB activity in a ligand-dependent manner utilizing a luciferase reporter gene system.7 Together, these results are the first demonstration of a rat ALX that is conserved in both structure and function suggesting that ALX plays key roles in regulating effector immune responses from murine to human species.