N-Formylated humanin activates both formyl peptide receptor-like 1 and 2

Harada, Masataka; Habata, Yugo; Hashimoto, Masaki; Nishi, K.; Fujii, Ryo; Kobayashi, Makoto; Hinuma, Shuji

doi:10.1016/j.bbrc.2004.09.046

Cited by 102 publications

(81 citation statements)

References 35 publications

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“…There are already a few FPRL1 ligands, such as peptides derived from the bacteria H. pylori [15] and the human neuroprotective factor, humanin [12], which also binds FPRL2 with low affinity. Interestingly, the N-formylated form of humanin was found to perform more potently as a ligand for FPRL1 than non-formylated humanin, and to be chemotactic for CHO cells expressing FPRL1 or FPRL2 [36]. The third mitochondrial peptide that we identified as an agonist for FPR and FPRL1 is an N-formylated peptide derived from the cytochrome c oxidase subunit 1.…”

Section: Discussionmentioning

confidence: 86%

Human mitochondria-derivedN-formylated peptides are novel agonists equally active on FPR and FPRL1, whileListeria monocytogenes-derived peptides preferentially activate FPR

2005

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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 (fMLKLIV) 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 EC 50 , in a Fura-2 calcium mobilization assay, of 10 nM, 44 nM, and 160 nM on FPRexpressing cells, and 15 nM, 55 nM and 120 nM on FPRL1-expressing cells. fMMYALF was also a low-affinity agonist of FPRL2 (EC 50 of 1 lM) 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.

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Section: Discussionmentioning

confidence: 86%

Human mitochondria-derivedN-formylated peptides are novel agonists equally active on FPR and FPRL1, whileListeria monocytogenes-derived peptides preferentially activate FPR

2005

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“…Indeed, FPRL2 does not respond to fMLP and the large variety of other FPR and FPRL1 ligands, unless at very high concentrations which are likely physiologically irrelevant. The only significant exception is the neuroprotective peptide humanin, which acts on both FPRL1 and FPRL2 with similar potency (15). FPRL2 is characterized by a specific high-affinity agonist, the peptide F2L, which is poorly active on FPRL1 and inactive on FPR (17).…”

Section: Discussionmentioning

confidence: 99%

“…For FPRL2, on the other hand, few specific ligands have been identified. A newly discovered peptide, humanin, neuroprotective in Alzheimer's disease models, was shown to bind FPRL2 and FPRL1 with high affinity (15,16). So far, the most specific ligand described for FPRL2 is the endogenous peptide F2L (17).…”

Section: Formyl Peptide Receptor-like 2 Is Expressed and Functional Imentioning

confidence: 99%

Formyl Peptide Receptor-Like 2 Is Expressed and Functional in Plasmacytoid Dendritic Cells, Tissue-Specific Macrophage Subpopulations, and Eosinophils

Devosse

Guillabert

D’Haene

et al. 2009

The Journal of Immunology

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The formyl peptide receptor (FPR) is a key player in innate immunity and host defense mechanisms. In humans and other primates, a cluster of genes encodes two related receptors, FPR-like 1 and FPR-like 2 (FPRL1 and FPRL2). Despite their high sequence similarity, the three receptors respond to different sets of ligands and display a different expression pattern in leukocyte populations. Unlike FPR and FPRL1, FPRL2 is absent from neutrophils, and two endogenous peptide agonists, F2L and humanin, were recently described. In the present work, we investigated the detailed functional distribution of FPRL2 in leukocytes by quantitative PCR, flow cytometry, immunohistochemistry, and chemotaxis assays, with the aim of raising hypotheses regarding its potential functions in the human body. We describe that FPRL2 is highly expressed and functional in plasmacytoid dendritic cells and up-regulated upon their maturation. FPRL2 is also expressed in eosinophils, which are recruited but do not degranulate in response to F2L. FPRL2 is expressed and functional in macrophages differentiated from monocytes in vitro in different conditions. However, in vivo, only specific subsets of macrophages express the receptor, particularly in the lung, colon, and skin, three organs chronically exposed to pathogens and exogenous aggressions. This distribution and the demonstration of the production of the F2L peptide in mice underline the potential role of FPRL2 in innate immunity and possibly in immune regulation and allergic diseases.

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“…Recently, a panoply of additional unrelated peptide agonists have been identified for FPR and FPRL1, including synthetic peptides, pathogen-derived peptides, and various host proteins and peptides (7,(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Only two naturally occurring peptide agonists have been identified to date for FPRL2: F2L and the neuropeptide humanin, both of which also activate FPRL1 (1,23).…”

Section: F Ormylpeptide Receptor (Fpr)mentioning

confidence: 99%

F2L, a Peptide Derived from Heme-Binding Protein, Chemoattracts Mouse Neutrophils by Specifically Activating Fpr2, the Low-Affinity N-Formylpeptide Receptor

Gao

Guillabert

et al. 2007

The Journal of Immunology

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F2L (formylpeptide receptor (FPR)-like (FPRL)-2 ligand), a highly conserved acetylated peptide derived from the amino-terminal cleavage of heme-binding protein, is a potent chemoattractant for human monocytes and dendritic cells, and inhibits LPS-induced human dendritic cell maturation. We recently reported that F2L is able to activate the human receptors FPRL-1 and FPRL2, two members of the FPR family, with highest selectivity and affinity for FPRL2. To facilitate delineation of mechanisms of F2L action in vivo, we have now attempted to define its mouse receptors. This is complicated by the nonequivalence of the human and mouse FPR gene families (three vs at least eight members, respectively). When cell lines were transfected with plasmids encoding the eight mouse receptors, only the one expressing the receptor Fpr2 responded to F2L (EC50 ∼400 nM for both human and mouse F2L in both calcium flux and cAMP inhibition assays). This value is similar to F2L potency at human FPRL1. Consistent with this, mouse neutrophils, which like macrophages and dendritic cells express Fpr2, responded to human and mouse F2L in both calcium flux and chemotaxis assays with EC50 values similar to those found for Fpr2-expressing cell lines (∼500 nM). Moreover, neutrophils from mice genetically deficient in Fpr2 failed to respond to F2L. Thus, Fpr2 is a mouse receptor for F2L, and can be targeted for the study of F2L action in mouse models.

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N-Formylated humanin activates both formyl peptide receptor-like 1 and 2

Cited by 102 publications

References 35 publications

Human mitochondria-derivedN-formylated peptides are novel agonists equally active on FPR and FPRL1, whileListeria monocytogenes-derived peptides preferentially activate FPR

Human mitochondria-derivedN-formylated peptides are novel agonists equally active on FPR and FPRL1, whileListeria monocytogenes-derived peptides preferentially activate FPR

Formyl Peptide Receptor-Like 2 Is Expressed and Functional in Plasmacytoid Dendritic Cells, Tissue-Specific Macrophage Subpopulations, and Eosinophils

F2L, a Peptide Derived from Heme-Binding Protein, Chemoattracts Mouse Neutrophils by Specifically Activating Fpr2, the Low-Affinity N-Formylpeptide Receptor

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