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*
Laboratory of Molecular Immunoregulation, Division of Basic Sciences, National Cancer Institute-Frederick Cancer Research and Development Center and
Intramural Research Support Program, Science Applications International Corp.-Frederick, Frederick, MD 21702; and
Department of Pharmacology, University of Illinois, Chicago, IL 60612
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In addition to bacterium- and tissue-derived chemoattractants, many synthetic peptides that exhibit chemotactic activity for leukocytes have been discovered. In fact, one of the most potent phagocyte chemotactic factors, fMLP, was synthesized even before its isolation from Gram-negative bacterial supernatants (1). These synthetic chemotactic peptides have become very useful probes for the study of leukocyte receptor expression and activation. Recently, WKYMVm, a hexapeptide isolated and modified from a peptide library, has been reported to be a very potent stimulant of several human leukocytic cell lines as well as peripheral blood neutrophils (6, 7, 8, 9). This peptide stimulated a typical STM receptor-mediated signaling pathway, including the activation of phospholipase C, phosphoinositide hydrolysis, and Ca2+ mobilization in target cells. Since the signaling of WKYMVm in human cells was not cross-desensitized by a number of known chemoattractants, including fMLP, C5a, platelet-activating factor, and the chemokine IL-8, it was postulated that this peptide may use an undefined leukocyte STM receptor (7, 8). Due to the high potency of WKYMVm in leukocyte activation, we considered it desirable to identify the leukocyte receptor(s) that might be utilized by this peptide and to explore its potential as a potent inducer of cell signaling and desensitization. In this study, we report that MKYMVm uses two STM receptors expressed by phagocytic leukocytes for its chemotactic and calcium (Ca2+)-mobilizing activity: the high affinity fMLP receptor FPR and the low affinity fMLP receptor FPRL1, which has been identified as an efficacious receptor mediating the chemotactic and Ca2+-mobilizing activity of serum amyloid A (SAA) (10, 11, 12) and a synthetic peptide domain of HIV-1 envelope gp41 (13). Since the peptide WKYMVm exhibits an extraordinarily high efficacy on FPRL1, it could be used as a very useful agent in the study of FPRL1 signaling.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The WKYMVm (Trp-Lys-Tyr-Met-Val-D -Met, designated W peptide) was synthesized and purified by the Department of Biochemistry, Colorado State University (Fort Collins, CO), according to the published sequence (7). The purity was greater than 90%, and the amino acid composition was verified by mass spectrometer. The endotoxin levels in the dissolved peptide were undetectable. The synthetic formyl peptide fMLP was purchased from Sigma (St. Louis, MO). Tritiated [3H]fMLP was purchased from Dupont NEN (Boston, MA).
Cells
The human PBMC were isolated from leukopacks through the courtesy of Transfusion Medicine Department, National Institute of Health Clinical Center (Bethesda, MD). Monocytes were further purified by elutriation to yield >90% pure preparations. Human neutrophils were purified from the same leukopacks by 3% dextran sedimentation with a purity of >98%. Rat basophilic leukemia cells stably transfected with epitope-tagged high affinity fMLP receptor FPR (designated ETFR cells) were a kind gift of Drs. H. Ali and R. Snyderman, Duke University (Durham, NC). Human embryonic kidney 293 cells stably expressing FPRL1 (designated FPRL1/293 cells) were a kind gift of Drs. P. M. Murphy and J.-L. Gao (National Institute of Allergy and Infectious Diseases, Bethesda, MD). All of the transfected cells were maintained in DMEM, 10% FCS, and 0.8 mg/ml geneticin (G418; Life Technologies, Rockville, MD).
Chemotaxis
Migration of leukocytes, ETFR, and FPRL1/293 cells was assessed using a 48-well microchemotaxis chamber technique, as previously described (14, 15, 16). Different concentrations of stimulants were placed in wells of the lower compartment of the chamber (Neuro Probe, Cabin John, MA); the cell suspension was seeded into wells of the upper compartment, which was separated from the lower compartment by a polycarbonate filter (Osmonics, Livermore, CA; 5 µm pore size for leukocytes, 10 µm pore size for ETFR and FPRL1/293 cells). The filters for ETFR and FPRL1/293 cell migration were precoated with 50 µg/ml collagen type I (Collaborative Biomedical Products, Bedford, MA) to favor cell attachment. After incubation at 37°C (90 min for monocytes, 60 min for neutrophils, and 300 min for ETFR or FPRL1/293 cells), the filters were removed and stained, and the number of cells migrating across the filter were counted by light microscopy after coding the samples. The experiments were performed at least five times with each cell type and the results are presented as the chemotaxis indexes (CI) representing the fold increase in the number of migrating cells in response to stimuli, over the spontaneous cell migration (in response to control medium). The CI of 1.8 or greater are statistically significant compared with cell migration in the absence of chemoattractant, as assessed by Student’s t test.
Calcium mobilization
Calcium mobilization was assayed by incubating 107/ml of monocytes, neutrophils, FPRL1, or FPR transfectants in loading buffer containing 138 mM NaCl, 6 mM KCl, 1 mM CaCl2, 10 mM HEPES (pH 7.4), 5 mM glucose, 0.1% BSA, with 5 µM fura 2 (Sigma) at 37°C for 30 min. The dye-loaded cells were washed and resuspended in fresh loading buffer. The cells were then transferred into quartz cuvettes (106 cells in 2 ml), which were placed in a luminescence spectrometer LS50 B (Perkin-Elmer Limited, Beaconsfield, U.K.). Stimulants at different concentrations were added in a volume of 20 µl to the cuvettes at indicated time points. The ratio of fluorescence at 340 and 380 nm wavelength was calculated using the FL WinLab program (Perkin-Elmer).
Binding assays
A single concentration of [3H]fMLP was added simultaneously with different concentrations of unlabeled fMLP or W peptide to a cell suspension (FPRL1/293 or ETFR, 2 x 106 cells/200 µl in RPMI 1640, 1% BSA, and 0.05% NaN3) in duplicate samples. The samples were incubated under constant rotation for 30 min at 37°C. After incubation, the samples were filtered onto Whatman GF/C discs (Whatman International, Kent, U.K.) on a 12-well manifold, followed by extensive washing with ice-cold PBS. The discs were air dried at 65°C, submerged in liquid scintillation mixture, and counted for ß emission.
Statistical analysis
Unless specified, all experiments were performed three to five times and the results presented are from representative experiments. The significance of the difference between test and control groups was analyzed with a Student’s t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A). The
chemotactic activity of W peptide was very potent and already evident
at picomolar concentrations for both monocytes and neutrophils. The
dose-response curves are bell shaped with maximal cell migration at low
nanomolar peptide concentrations. We next examined whether phagocyte
migration induced by W peptide was based on chemotaxis or chemokinesis.
Checkerboard analyses showed that monocytes migrated well only when
higher concentrations of W peptide were present in the lower wells of
the chemotaxis chamber (Table I). There
was no increased cell migration when higher concentrations of W peptide
were present in the upper wells. Equal concentrations of W peptide in
both upper and lower wells induced a slight but significant increase in
cell migration. These results suggest that the cell migration induced
by W peptide was mainly due to a chemotactic effect with a minor
contribution of chemokinesis.
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B) or herbimycin A (data not shown), suggesting
that a Gi protein-coupled receptor was involved
(2, 3, 4, 5, 17, 18, 19). This was supported by the potent induction
of a dose-dependent, and pertussis toxin-sensitive,
Ca2+ mobilization in monocytes and neutrophils by
W peptide (Fig. 2, A and
E, and data not shown). In agreement with the chemotactic
activity, the Ca2+-mobilizing activity of W
peptide was also significant at picomolar concentrations. These results
confirm the original reports that W peptide is a potent activator of
phagocytic cells (6, 7, 8, 9) and extended the observation of
function of this peptide as a chemoattractant of monocytes and
neutrophils.
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, IL-8, and stromal
cell-derived factor 1, or vice versa (data not shown), suggesting W
peptide does not share a receptor with any of these chemokines. Low
concentrations (in nM range) of fMLP also had a limited effect on W
peptide-induced Ca2+ flux (Fig. 2, B
and F). This is in agreement with the previous reports that
fMLP in such concentration range did not desensitize the cell response
to W peptide (7, 8). However, when the concentrations of
fMLP were increased to the micromolar range, the cell response to W
peptide in monocyte (Fig. 2C) or neutrophils (Fig. 2G) was significantly attenuated. Moreover, W peptide was
able to desensitize the Ca2+ flux response to
103–104-fold higher concentrations of fMLP in
both monocytes (Fig. 2D) and neutrophils (Fig. 2H). These results strongly suggest that W peptide shares
receptor(s) with fMLP on human phagocytic cells and activates the
receptor(s) with much higher efficacy than fMLP.
Since fMLP was known to induce Ca2+ flux through
at least two STM, G protein-coupled receptors, the high affinity FPR
and the low affinity FPRL1 (4, 17, 20), we tested the
effect of W peptide on these two receptors transfected and
overexpressed in human cells that originally were not responsive to
fMLP stimulation. fMLP over a wide range of concentrations induced
Ca2+ mobilization in an FPR-transfected rat
basophilic leukemia cell line (ETFR cells), with a minimal effective
dose at 10-10 M (Fig. 3A). In contrast, the minimal
effective concentration for fMLP to induce Ca2+
mobilization in FPRL1-transfected cells (FPRL1/293 cells) was in the
µM range (Fig. 3E). These results confirmed the previous
conclusion that FPR is a high affinity receptor for fMLP, whereas FPRL1
has much lower affinity for fMLP (4, 17, 20). The W
peptide also induced Ca2+ mobilization in cells
transfected with either of these receptors (Fig. 3, B and
F). However, the minimal effective doses for W peptide to
activate both FPR and FPRL1 were at 10-11 M,
suggesting that W peptide activate these receptors with higher
efficacy. This was further supported by cross-desensitization of
Ca2+ flux between W peptide and fMLP in both
receptor transfectants. As shown in Fig. 3, G and
H, although sequential stimulation of the cells expressing
FPRL1 with W peptide and fMLP resulted in bidirectional
desensitization, a 105-fold excess of fMLP was
required to desensitize the effect of W peptide in FPRL1/293 cells.
Likewise, in ETFR cells, with equal concentrations, W peptide also more
potently desensitized the effect of fMLP (Fig. 3, C and
D). In control experiments, W peptide and fMLP did not
induce any Ca2+ mobilization in parental or
mock-transfected rat basophilic cell line and human embryonic kidney
293 cells (data not shown). Our results indicate that W peptide
activates both FPR and FPRL1 with high potency, whereas fMLP is a
highly efficacious agonist only for FPR.
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1 pM (Fig. 4, A and
B), but these cells failed to migrate in response to a wide
concentration range of fMLP (Fig. 4, A and B). On
the other hand, both fMLP and W peptide induced the migration of the
ETFR cells with comparable dose-response curves (Fig. 4, A
and C). These chemotaxis experiments indicate that fMLP is
only a partial and low affinity agonist for FPRL1 since it does not
induce migration of FPRL1-expressing cells. W peptide, on the other
hand, appears to be a very efficient agonist for both FPR and FPRL1,
with even higher efficacy for FPRL1 than FPR, as low picomolar
concentrations of W peptide are sufficient to induce both
Ca2+ flux and chemotaxis in these cells. As
observed with phagocytic cells, the migration of FPRL1/293 and ETFR
cells induced by W peptide was also inhibited by pretreatment of the
cells with pertussis toxin (Fig. 4D and data not shown). To further
confirm that W peptide shares receptors with fMLP, we used
ligand-binding competition experiments with
3H-labeled fMLP. In agreement with the
chemotactic and Ca2+ mobilization activity for
the ETFR cells, W peptide effectively competed with
[3H]fMLP for binding to ETFR cells (Fig. 5). [3H]fMLP did
not significantly bind to FPRL1/293 cells, presumably due to its low
affinity for FPRL1 (Fig. 5).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Leukocyte infiltration at the sites of inflammation in vivo is believed to be a consequence of cell migration toward a gradient of chemoattractant(s), either derived from microorganisms or the local tissues. The discovery of synthetic N-formyl oligopeptide chemoattractants for phagocytes greatly facilitated the study of leukocyte locomotion (1). Several natural N-formyl peptide chemoattractants, including the prototype fMLP, have subsequently been purified from bacterial supernatants, providing evidence in support of them being biologically relevant ligands for formyl peptide receptors on phagocytic cells. Mitochondrial proteins are also N formylated and are chemotactic for neutrophils (21), and thus may constitute an endogenous source of chemotactic peptides released by damaged tissue. Although the N-formyl group was considered essential for optimal agonist potency (22), nonformylated peptides may also attract and activate phagocytes (4, 17). The prototype receptor for formyl peptides designated FPR is expressed by neutrophils and monocytes and was cloned several years ago (4, 17). FPR was subsequently shown to have a much broader spectrum of agonists than initially expected. In fact, the synthetic pentapeptide Met-Nle-Leu-Phe-Phe-OH, either N formylated or N acetylated, is more potent than the parental prototype fMLP in the induction of Ca2+ flux in human neutrophils (19). Amino-terminal urea-substituted and carbamate-modified peptides are also potent agonists for FPR (23, 24). In our study, W peptide does not contain any modification groups at the N terminus, yet exhibits comparable Ca2+-mobilizing and chemotactic activity as fMLP on FPR. These observations support the hypothesis derived from structural analysis of FPR that the binding pocket of this receptor is able to accommodate larger amino-terminal groups (23, 24), accounting for the capacity of this receptor to interact with a great variety of endogenously derived as well as exogenous peptide ligands.
FPRL1 was cloned from human phagocytic cells (20, 25, 26, 27)
and a genomic library (28). FPRL1 possesses 69% identity
at the amino acid level to FPR (18, 19), and both
receptors are expressed by monocytes and neutrophils and are clustered
on human chromosome 19q13 (28, 29). While fMLP is a high
affinity agonist for FPR, it interacts with and induces
Ca2+ flux in FPRL1 only at high concentrations
(Fig. 3E and Refs. 20, 26, 29) and did not
induce significant migration of FPRL1/293 cells at a wide range of
concentrations tested (Fig. 4B and Ref. 10). In
addition, [3H]fMLP bound only to FPR, but not
to FPRL1-transfected cells, as shown in this study. Thus, fMLP is not
an efficacious agonist for FPRL1. In contrast, W peptide, although also
activating both FPR and FPRL1, showed a much higher efficacy than fMLP
on FPRL1 and induced migration and Ca2+ flux in
FPRL1/293 cells at low picomolar concentrations, suggesting W peptide
has even greater efficacy on FPRL1 than on FPR. This may also explain
the failure for fMLP to desensitize
Ca2+-mobilizing activity in phagocytes when W
peptide was used at high nanomolar concentrations (7).
FPRL1 is expressed by a variety of cell types, including monocytes,
neutrophils, and cells other than the hemopoietic origin, such as
hepatocytes (17). The expression of this receptor was also
highly inducible in epithelial cells by selected cytokines such as
IL-13 and IFN-
(30). Since W peptide was also reported
to promote phosphoinositol hydrolysis in B lymphoma cells
(7), we tested the chemotactic activity of this peptide on
peripheral B cells and found a significant migration of B cells in
response to low nanomolar concentrations of W peptide (data not shown).
Preliminary experiments suggest that human B lymphocytes express FPRL1,
but not FPR transcripts (Le et al., data not shown). Due to the
expression of FPRL1 in a great variety of cell types, it may play an
important role in inflammatory and immunological responses. In support
of this hypothesis, we recently identified FPRL1 to be a functional
receptor for a normal serum protein, SAA (10), which
increases its concentration by up to several hundred-fold during acute
phase responses, and is a potent phagocyte chemoattractant and
activator (11, 12). We also identified several synthetic
peptide domains derived from HIV-1 envelope proteins as activators of
FPRL1 (13, 31). Moreover, several peptides derived from a
plasmid-based random library have been shown also to be highly
efficacious agonists for FPRL1 (32). However, W peptide
does not bear any significant sequence homology to either fMLP, SAA, or
HIV-1 envelope protein domains. Therefore, FPRL1, like its prototype
FPR, has the capacity to interact with a broad spectrum of
agonists.
In addition to peptide and protein agonists, a lipid metabolite lipoxin A4 (LXA4) has been reported to be a high affinity ligand and potent agonist for FPRL1 (also thus termed LXA4R) (33). LXA4 is an eicosanoid generated during a number of host reactions such as inflammation, thrombosis, and atherosclerosis, and was initially discovered as an inhibitor of immune responses (reviewed in Ref. 34). LXA4 was subsequently reported to inhibit neutrophil chemotaxis (35) and transepithelial migration induced by chemotactic agents (36). LXA4 bound to CHO cells transfected with FPRL1(LXA4R) with high affinity and increased GTPase activity and the release of esterified arachidonate (33). Thus, LXA4 has been proposed to be an endogenously produced ligand for FPRL1 (33, 37). Although LXA4 has not been documented to induce Ca2+ mobilization in neutrophils or FPRL1-transfected cells (33), it was reported to induce Ca2+ flux and chemotaxis in monocytes presumably through FPRL1 (38, 39). Based on these observations, differential activation of second messengers in monocytes vs neutrophils by LXA4 was postulated. Further study is needed to elucidate the structural basis for the interaction of FPRL1 with unrelated protein/peptide ligands such as W peptide, SAA, HIV-1 envelope protein domains, and fMLP, vs the lipid ligand LXA4.
The signal transduction pathways utilized by FPRL1 have not been extensively studied. However, the high level of homology to FPR, sensitivity to inhibition by pertussis toxin, and potent induction of phagocyte migration and activation by their agonists suggest that FPRL1 and FPR may share many signal transduction steps following activation. The binding of FPR by agonists results in a G protein-mediated signaling cascade, which results in cell adhesion, chemotaxis, release of oxygen intermediates, enhanced phagocytosis, and bacterial killing, as well as mitogen-activated protein kinase activation and increased gene transcription (4, 17). Activation by fMLP can lead to heterologous desensitization of the subsequent cell response to other G protein receptor ligands (40, 41), including chemokines. In our previous study, incubation of human monocytes with a synthetic FPRL1-specific peptide domain of HIV-1 gp120 resulted in down-regulation of chemokine receptors CCR5 and CXCR4 (31), and a reduced cell response to a number of chemoattractants (12). It is therefore reasonable to propose that activation of FPRL1 by W peptide may also activate signaling events that culminate in heterologous desensitization of other G protein-coupled chemotactic receptors. Whether W peptide will be potent desensitizer of CCR5 and CXCR4 thus inhibits M-tropic or T-tropic HIV fusion/entry is being investigated.
After studies of considerable number of peptide variants, W peptide has been identified as one of the most potent activators of phagocyte chemotaxis and Ca2+ flux, in addition to reported activation of phospholipase D, phosphoinositide hydrolysis, and bacterial killing of phagocytes (6, 7, 8, 9). In receptor-transfected cells, W peptide showed similar potency as fMLP in activating FPR, but it is far more potent than fMLP in activating FPRL1. In fact, among the chemotactic and Ca2+-mobilizing agonists identified to date for FPRL1 in this laboratory, W peptide is the most efficacious, acting at picomolar concentrations. Therefore, this peptide will provide a very useful probe for the study of leukocyte receptor expression, activation, and desensitization. Furthermore, immunomodulatory agents can be designed based on the structure-function property of W peptide.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Ji Ming Wang, LMI, DBS, NCI-FCRDC, Building 560, Room 31-40, Frederick, MD 21702-1201. E-mail address:
3 Abbreviations used in this paper: STM, seven-transmembrane; CI, chemotaxis index; FPR, formyl peptide receptor; FPRL1, formyl peptide receptor-like 1; LXA4, lipoxin A4; SAA, serum amyloid A.
Received for publication July 30, 1999. Accepted for publication October 6, 1999.
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