Human mitochondria-derived N-formylated peptides are novel agonists equally active on FPR and FPRL1, while Listeria monocytogenes-derived peptides preferentially activate FPR
Human mitochondria-derived N-formylated peptides are novel agonists equally active on FPR and FPRL1, while Listeria monocytogenes-derived peptides preferentially activate FPR
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DOI：
10.1002/eji.200526338
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发表时间：
2005-08-01
影响因子：
5.4
通讯作者：
Boulay, F
中科院分区：
文献类型：
--
作者：
Rabiet, MJ;Huet, E;Boulay, F
n -甲酰基肽是细菌和线粒体蛋白的裂解产物，可以吸引白细胞到感染或组织损伤的部位。本研究利用表达人n -甲酰基肽受体FPR或其两个同源物（FPRL1、FPRL2）的HL-60细胞系，测定了源自单核增生李斯特菌或人线粒体蛋白的n -甲酰基肽的受体选择性。细菌肽对FPR的作用是FPRL1的100倍，而它们都不能通过FPRL2触发细胞内信号传导。相比之下，线粒体NADH脱氢酶亚基4 （fMLKLM）和6 (fMMYALF) N端对应的N-甲酰基化六肽和细胞色素c氧化酶亚基I （fMFADRW）对FPR和FPRL1的作用相同。它们以以下效力顺序触发细胞反应：fMMYALF > fMLKLIV > fMFADRW，在Fura-2钙动员实验中，fpr表达细胞的EC50为10 nM、44 nM和160 nM， fprl1表达细胞的EC50为15 nM、55 nM和120 nM。fMMYALF也是FPRL2的低亲和力激动剂（EC50为1 μ M），对表达FPRL1和FPRL2的细胞都具有趋化作用。我们发现了一种新的线粒体宿主来源的人类n -甲酰基肽受体激动剂，可能在炎症或退行性过程中发挥作用。
N-formyl peptides are cleavage products of bacterial and mitochondrial proteins, and can attract leukocytes to sites of infection or tissue damage. In this study, HL-60 cell lines expressing the human N-formyl peptide receptor FPR or its two homologues (FPRL1, FPRL2) were used to determine the receptor selectivity of N-formylated peptides derived from Listeria monocytogenes or from human mitochondrial proteins. Bacterial peptides were 100-fold more potent on FPR than on FPRL1, whereas none of them could trigger intracellular signaling through FPRL2. In contrast, N-formylated hexapeptides corresponding to the N terminus of mitochondrial NADH dehydrogenase subunits 4 (fMLKLM and 6 (fMMYALF), and cytochrome c oxidase subunit I (fMFADRW) were equally potent on FPR and FPRL1. They triggered cellular responses with the following order of potency: fMMYALF > fMLKLIV > fMFADRW, with an EC50, in a Fura-2 calcium mobilization assay, of 10 nM, 44 nM, and 160 nM on FPR-expressing cells, and 15 nM, 55 nM and 120 nM on FPRL1-expressing cells. fMMYALF was also a low-affinity agonist of FPRL2 (EC50 of 1 mu M) and was chemotactic for both FPRL1- and FPRL2-expressing cells. We identified novel mitochondrial host-derived agonists for human N-formyl-peptide receptors that might play a role in inflammatory or degenerative processes linked to their stimulation.