The Synthetic Peptide Trp-Lys-Tyr-Met-Val-D-Met Inhibits Human Monocyte-Derived Dendritic Cell Maturation via Formyl Peptide Receptor and Formyl Peptide Receptor-Like 2

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We determined the expression of the formyl peptide receptor (FPR) family and the functional roles of the FPR family in NK cells. All tested human NK cells express two members of the FPR family (FPR1 and FPR2). The expression of FPR3 was noted to occur in a donor-specific manner. The stimulation of NK cells with FPR family-selective agonists (fMLF (N-formyl-Met-Leu-Phe), MMK-1, F2L, and WKYMVm (Trp-Lys-Tyr-Met-Val-d-Met)) elicited cytolytic activity in resting NK cells, but not in IL-2-activated NK cells; the cytolytic activity was not inhibited by pertussis toxin. The FPR family agonists also stimulated chemotactic migration of IL-2-activated NK cells, but not resting NK cells; the chemotactic migration was completely inhibited by pertussis toxin. WKYMVm stimulates ERK, p38 MAPK, and JNK activities in both resting and IL-2-activated NK cells. WKYMVm-induced chemotactic migration was partially inhibited by PD98059 (2′-amino-3′-methoxyflavone); however, the inhibition of JNK by its selective inhibitor (SP600125, anthra[1,9-cd]pyrazol-6(2H)-one) dramatically inhibited the WKYMVm-induced cytolytic activity. Furthermore, WKYMVm-induced chemotactic migration and cytolytic activity were partly inhibited by FPR family-selective antagonists (cyclosporin H and WRWWWW). Taken together, our findings indicate that human NK cells express functional members of the FPR family, and in turn the activation of the three members of the FPR receptor family elicit cytolytic activity in NK cells, thus suggesting that the receptors are potentially important therapeutic targets for the modulation of NK cell-mediated immune responses.

Section: Discussionsupporting

confidence: 48%

Functional Expression of Formyl Peptide Receptor Family in Human NK Cells

Kim

et al. 2009

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“…F2L binds and activates the human G protein-coupled receptors FPRL-1 and FPRL2, members of the FPR family, in the low micromolar and low nanomolar range, respectively, and chemoattracts human monocytes and dendritic cells, which are known to express FPR, FPRL1 and -2, and FPR and FPRL2, respectively (1,4,5). F2L also inhibits LPS-induced dendritic cell maturation (6). These findings suggested that F2L might play a role in the initiation and/or regulation of immune responses, a hypothesis that may be tested in part by analyzing F2L receptors in animal models.…”

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

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.

“…When tested on monocytes and monocyte-derived DCs, F2L promotes calcium mobilization and chemotaxis (17). F2L inhibits the IL-12 production promoted by LPS in DCs and appears therefore to be an inhibitor of DC maturation (18).…”

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 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.