(Journal of Leukocyte Biology. 2001;70:155-161.)
© 2001
by Society for Leukocyte Biology
Synthetic peptide MMK-1 is a highly specific chemotactic agonist for leukocyte FPRL1
Jin Yue Hu*,
,
Yingying Le*,
Wanghua Gong
,
Nancy M. Dunlop*,
Ji Liang Gao
,
Philip M. Murphy and
Ji Ming Wang*
* Laboratory of Molecular Immunoregulation, Division of Basic Sciences, National Cancer Institute-Frederick Cancer Research and Development Center, and
The Intramural Research Support Program, SAIC Frederick, Frederick, Maryland;
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland; and
Cancer Research Institute, Hunan Medical University, Changsha, China
Correspondence: Dr. Ji Ming Wang, LMI, DBS, NCI-FCRDC, Building 560, Room 31-40, Frederick, MD 21702-1201. E-mail:
wangji{at}mail.ncifcrf.gov
 |
ABSTRACT
|
|---|
Human phagocytic leukocytes express the seven-transmembrane
G-protein-coupled receptors formyl peptide receptor (FPR) and FPR-like
1 (FPRL1). MMK-1, a synthetic peptide derived from a random peptide
library, is reported to induce calcium mobilization specifically in
human FPRL1 gene-transfected cells. However, its actions on
human phagocytic leukocytes remain poorly defined. We found that MMK-1
is a potent chemotactic and calcium-mobilizing agonist for human
monocytes, neutrophils, and FPRL1-transfected human embryonic kidney
(HEK) 293 cells but is inactive in cells transfected with FPR. MMK-1
also activated HEK 293 cells transfected with FPR2, a mouse
counterpart of human FPRL1. Furthermore, MMK-1 increased
pertussis toxin-sensitive production of inflammatory cytokines in human
monocytes. MMK-1 signaling in human phagocytes was completely
desensitized by a well-defined FPRL1 agonist, suggesting that
FPRL1 is likely a receptor that mediates the action of MMK-1 in primary
cells. Since MMK-1 is one of the most potent FPRL1-specific agonists
identified so far, it can serve as a modulator of the host
defense and a useful agent for further studying the signaling and
function of FPRL1.
Key Words: phagocyte • chemotaxis • Ca2+ mobilization • cytokines
|
INTRODUCTION
|
|---|
Leukocytes respond to a large number of chemoattractants by
directional cell movement, activation of integrins, and production of
proinflammatory mediators. These chemoattractants include chemokines
and the "classical" chemoattractants such as N-formyl
methionyl-leucyl-phenylalanine (fMLF), the activated complement
fragment 5, leukotriene B4, and platelet-activating factor
[1
2
3
4
5
6
]. Both chemokines and the classical chemotactic
factors function by binding and activating G-protein-coupled,
seven-transmembrane receptors on leukocytes [4
5
6
]. It
is believed that mobilization of phagocytes in response to chemotactic
factors constitutes the first line of host defense in inflammation and
infection.
fMLF is one of the first "classical" chemoattractants studied.
Initially it was tested as part of a series of synthetic peptides under
evaluation for chemotactic activity, and later it was purified from
Escherichia coli culture supernatant [2
,
7
]. In humans, two fMLF receptor genes have been cloned,
which encode a high-affinity receptor formyl peptide receptor (FPR)
[8
] and a low-affinity receptor FPR-like 1 (FPRL1)
[9
]. In addition to the bacterium-derived fMLF, a number
of synthetic peptide agonists have been identified for FPR
[10
]; however, the host-derived agonists for this
receptor have not been defined. In contrast, an endogenously derived
lipid metabolite lipoxin A4 (LXA4) has been reported to bind FPRL1 with
high affinity [11
]. Furthermore, a proinflammatory
acute-phase protein, serum amyloid A, has been shown to induce
phagocyte migration and calcium mobilization through FPRL1
[12
13
14
]. These results suggest that by interacting with
host-derived agonists, FPRL1 may play important pathophysiological
roles in addition to participating in host defense against bacterial
invasion.
Recently, construction and screening of random peptide libraries have
become a useful approach to developing biologically active agents with
pharmaceutical potential. Klein et al. [15
] isolated a
number of small peptide sequences from a peptide library that could
react with FPR and FPRL1. One of these, named MMK-1 (LESIFRSLLFRVM),
appears to induce calcium mobilization with high efficacy in human
cells transfected with FPRL1 but with very low efficacy on
FPR-transfected cells. However, whether MMK-1 can activate native human
phagocytic cells or acts as a chemotactic agonist for FPRL1 has not
been reported. In this study we demonstrate that MMK-1 is a chemotactic
peptide for both human neutrophils and monocytes and is one of the most
potent and specific chemotactic agonists identified so far for FPRL1.
|
MATERIALS AND METHODS
|
|---|
Reagents
MMK-1 was synthesized and purified at the Department of
Biochemistry, Colorado State University (Fort Collins), according to
the published sequence [15
]. The purity was >90%, and
the amino acid composition was verified by mass spectrometry. The
endotoxin levels in the dissolved peptide were undetectable. Synthetic
fMLF was purchased from Sigma (St. Louis, MO).
Cells
Human peripheral blood mononuclear cells (PBMCs) were isolated
from leukopacks obtained from the Transfusion Medicine Department,
National Institutes 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 dextran
sedimentation with a purity of >98%. Rat basophilic leukemia cells
stably transfected with epitope-tagged human FPR (ETFR) were a kind
gift of H. Ali and R. Snyderman, Duke University (Durham, NC). Human
FPRL1 cDNA and mouse FPR2 were cloned and stably transfected into human
embryonic kidney (HEK) 293 cells as reported previously
[14
, 16
]. All transfected cells were
maintained in Dulbecco’s modified eagle’s medium, 10% fetal calf
serum, and 0.8 mg/mL of geneticin (G418; Gibco-BRL, Rockville, MD).
Chemotaxis assays
Migration of leukocytes and receptor-transfected cells was
assessed using a 48-well microchemotaxis chamber technique as
previously described [14
]. Different concentrations of
stimulants were placed in wells of the lower compartment of the chamber
(Neuro Probe, Cabin John, MD). 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-diameter pore size for leukocytes, 10-µm-diameter pore-size for
ETFR and 293 cells). The filters for migration of
receptor-transfected cells were precoated with 50 µg/mL of 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 transfectants), the filters were
removed and stained, and the numbers of cells migrating across the
filters were counted by light microscopy after the samples were coded.
Results are presented as the chemotaxis indexes (CIs) representing the
fold increase in the number of migrating cells in response to stimuli
over the spontaneous cell migration (in response to control medium).
Calcium mobilization
Calcium mobilization was assayed by incubating 107
cells/mL in loading buffer containing 138 mM NaCl, 6 mM KCl, 1 mM
CaCl2, 10 mM HEPES (pH 7.4), 5 mM glucose, 0.1% bovine
serum albumin, and 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 (106/2
mL) which were placed in a luminescence spectrometer LS50 B
(Perkin-Elmer Ltd., Beaconsfield, England). 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
wavelengths was calculated using the FL WinLab program (Perkin-Elmer).
Binding assays
The radioiodinated synthetic peptide WKYMVm
(125I-labeled W peptide) was kindly provided by W. Yieh,
NEN Lifesciences (Boston, MA). A single concentration of
125I-labeled W peptide was added simultaneously with
different concentrations of unlabeled W peptide, fMLF, or MMK-1 to a
cell suspension (human monocytes and FPRL1/293 cells or ETFR
cells, 1–2 x 106 cells/200µL RPMI 1640 containing
1% bovine serum albumin and 0.05% NaN3) in duplicate
samples in Eppendorf tubes. The samples were incubated under constant
rotation for 30 min at room temperature. After incubation, the samples
were centrifuged through a 10% sucrose-PBS cushion, and the tips of
the tubes containing cell pellets were counted for 
-ray emissions.
Cytokine production
Monocytes were preincubated with or without 50 ng/mL of
pertussis toxin (PT) at 37°C for 4h, then were incubated with
stimulants for another 24 h. Supernatants were collected,
centrifuged, and measured for IL-1ß and IL-6 by enzyme-linked
immunosorbent assay (R & S Systems, Minneapolis, MN).
Statistical analysis
Unless otherwise 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.
|
RESULTS
|
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We first verified the capacity of synthetic MMK-1 to induce
calcium mobilization in cell lines transfected with either FPR or
FPRL1. As shown in Figure 1A
, MMK-1 induced calcium mobilization in human FPRL1-transfected
HEK 293 (FPRL1/293) cells with a 50% effective concentration (EC50) at
2 nM. This is in agreement with the reported potency of this peptide on
FPRL1 [15
]. As expected, MMK-1-induced calcium
mobilization was attenuated by prior stimulation of the cells with a
high concentration (10-4 M) of fMLF and vice versa (Fig. 1B
and 1C)
. In addition, the MMK-1 signaling in FPRL1/293 cells was
cross-desensitized by a previously defined FPRL1 peptide agonist, F
peptide (F pep) [17
] (Fig. 1D
and 1E)
. No calcium
mobilization was elicited in FPR-expressing ETFR cells by MMK-1 over a
wide concentration range (Fig. 1F)
. However, ETFR cells exhibited
robust calcium flux responses to fMLF (Fig. 1G)
. These results
confirmed that the peptide specifically activates FPRL1. Because it is
unknown whether MMK-1 also activates human native phagocytic cells,
which are known to express FPRL1 [18
], we next tested
the effect of this peptide on phagocyte functions. Figure 2
shows that MMK1 induced dose-dependent calcium mobilization in
both human monocytes (Fig. 2A)
and neutrophils (Fig. 2D)
with EC50s in
the low-nanomolar range. The MMK-1-induced Ca2+ flux in
human phagocytic cells was also desensitized by pre-exposure of the
cells to the defined FPRL1 agonist F pep (Fig. 2B
and 2E)
but not to the
specific FPR agonist peptide T20 [19
] (Fig. 2C
and 2F)
,
suggesting that MMK-1 shares with F pep FPRL1 in primary phagocytic
leukocytes.
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Figure 1. Calcium mobilization induced by MMK-1 in FPRL1/293 and ETFR cells. (A)
Stimulation of FPRL1/293 cells by different concentrations of MMK-1. (B
and C) Sequential stimulation of FPRL1/293 cells with fMLF and MMK-1 or
vice versa. (D and E) Cross-desensitization of MMK-1 signaling in
FPRL1/293 cells by F peptide (F pep). F and G: stimulation of ETFR
cells by different concentrations of MMK-1 or fMLF.
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Figure 2. Calcium mobilization induced by MMK-1 in human phagocytes. (A)
Signaling of MMK-1 in human monocytes. (B) Cross-desensitization of
MMK-1 signaling in monocytes by F pep. (C) Sequential stimulation of
monocytes with T20 and MMK-1, and vice versa. (D) Signaling of MMK-1 in
human neutrophils. (E) Cross-desensitization of MMK-1 signaling in
neutrophils by F pep. (F) Sequential stimulation of neutrophils by T20
and MMK-1, and vice versa.
|
|
Because leukocyte migration and accumulation are considered the first
steps in host defense against invading pathogens, we investigated
whether MMK-1 could induce cell migration through FPRL1. As shown in
Figure 3
, MMK-1 induced considerable migration of both human monocytes
(Fig. 3A)
and neutrophils (Fig. 3B)
starting at concentrations of 1 nM
(EC50, 10 nM). The dose response of phagocyte migration to MMK-1 was
bell shaped and was inhibited by PT but not herbimycin A (HA) (Fig. 3C)
, suggesting the involvement of a G-protein-coupled chemotactic
receptor. The phagocyte migration induced by MMK-1 was dependent on the
concentration gradient of the peptide as examined by checkerboard
analysis (Table 1
), indicating that the effect of MMK-1 is chemotactic rather than
chemokinetic. Furthermore, MMK-1 also induced significant migration of
FPRL1/293 cells with a maximal response at 10 nM (Fig. 4A
). The parental HEK 293 cells (data not shown) and cells
expressing FPR (Fig. 4B) showed no migration in response to a wide
range of MMK-1 concentrations. These results suggested that FPRL1 is
likely a receptor mediating the leukocyte chemotactic activity of
MMK-1.
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Figure 3. Chemotactic activity of MMK-1 for human monocytes and neutrophils. (A
and B) Fold increase of monocyte or neutrophil migration in response to
MMK-1. *P < 0.05 compared with migration of cells in
response to medium alone. (C) Effects of PT or HA on monocyte migration
in response to MMK-1. Monocytes were preincubated with 100 ng/mL of PT
at 37°C for 30 min or 200 µM HA at 37°C for 2 h, then were
washed and examined for migration induced by MMK-1. fMLF at
10-7 M was used as control. *P < 0.05
compared with migration of cells incubated with medium alone.
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Figure 4. Chemotactic activity of MMK-1 for FPRL1/293 and ETFR cells. (A) Fold
increase of FPRL1/293 cell migration in response to MMK-1 over control
medium. (B) Lack of chemotactic activity of MMK-1 for FPR expressing
ETFR cells. fMLF at 10-7 M was used as control.
*P < 0.05 compared with spontaneous migration to
control medium.
|
|
To characterize the binding capacity of MMK-1 to its receptor, we used
a radioiodinated synthetic peptide—125I-labeled W peptide.
Our previous study indicated that W peptide activates both human FPR
and FPRL1 but activates FPRL1 with higher efficacy [20
].
Human monocytes showed a high level of binding for
125I-labeled W peptide, which was specifically displaced by
unlabeled W peptide (Fig. 5A
). Unlabeled fMLF or MMK-1 alone only partially displaced W
peptide binding to monocytes. However, the presence of a combination of
unlabeled fMLF and MMK-1 resulted in a displacement of
125I-labeled W peptide binding on monocytes at the level
comparable with that of unlabeled W peptide. Consistent with this, as
shown in Figure 5B
and 5C
, 125I-labeled W peptide bound to
both FPRL1- and FPR-transfected cells with high efficacy, and the
binding was completely displaced by unlabeled W peptide. However, in
FPRL1/293 cells, MMK-1 but not fMLF showed a complete inhibition of
125I-labeled W peptide binding, and fMLF efficiently
competed for 125I-labeled W peptide binding only in cells
expressing FPR. Thus, ligand-binding results provided additional
evidence to support the notion that MMK-1 uses FPRL1 in human cells.
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Figure 5. Displacement of 125I-labeled W peptide binding to FPRL1 by
MMK-1. 125I-labeled W peptide was incubated for 30 min at
room temperature with human monocytes (A), FPRL1/293 cells (B), or
FPR-expressing ETFR cells (C) in the presence of unlabeled W peptide,
fMLF, or MMK-1. The cells were then centrifuged through a sucrose-PBS
cushion and measured for radioactivity with a -ray counter.
|
|
We then investigated whether MMK-1 might also serve as a chemotactic
and activating agonist for the murine (m) counterpart of human FPRL1.
Several genes encoding putative mfMLF receptors have been identified
and cloned. mFPR1 is most homologous to human FPR, whereas mFPR2 is
most similar to human FPRL1 [5
, 21
]. We
therefore tested the effect of MMK-1 on HEK 293 cells transfected to
express mFPR1 and mFPR2. As shown in Figure 6
, MMK-1 induced marked calcium mobilization in mFPR2-transfected
cells (EC50 =1 nM) (Fig. 6A)
. The calcium mobilization induced by
MMK-1 in mFPR2/293 cells was attenuated by a high concentration of fMLF
(Fig. 6B
and 6C) , as well as by the human FPRL1-specific agonist F pep
(Fig. 6D and 6E)
. No calcium mobilization was induced by MMK-1 in
mFPR1-transfected cells at any concentration tested (Fig. 6F)
, whereas
fMLF induced a dose-dependent Ca2+ flux in these cells
(Fig. 6G)
. In addition, MMK-1 induced a potent chemotactic response of
mFPR2-transfected cells at low concentrations with an optimal cell
response to 10 nM peptide (Fig. 7
). MMK-1 did not induce migration of the HEK 293 cells expressing
mFPR1. Thus MMK-1 specifically activated mFPR2, the murine homologue of
human FPRL1.
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Figure 6. Calcium mobilization induced by MMK-1 in mFPR2/293 cells. (A)
Ca2+ flux induced by different concentrations of MMK-1in
mFPR2/293 cells. (B and C) Sequential stimulation of mFPR2/293 cells
with fMLF and MMK-1 or vice versa. (D and E) Cross-desensitization of
MMK-1 signaling in mFPR2/293 cells by F pep. (F and G) Response of
mFPR1/293 cells to MMK-1 or fMLF.
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Figure 7. Chemotactic activity of MMK-1 for mFPR2/293 and mFPR1/293 cells. (A)
Migration of mFPR2/293 cells in response to MMK-1. (B) Lack of
chemotactic activity of MMK-1 for mFPR1/293 cells. fMLF at
10-7 M was used as control. *P < 0.05
compared with spontaneous migration.
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|
The biologic activity of MMK-1 was further tested for its ability to
modulate the production of proinflammatory cytokines in human
monocytes. Monocytes stimulated with MMK-1 showed a significant
increase in production of interleukin (IL)-1ß and IL-6, and the
effect of the peptide was inhibited when the cells were pretreated with
PT. Another known FPRL1 agonist, F pep [17
], also
enhanced production of IL-1ß and IL-6 in monocytes, and the effect of
F pep was abolished by PT (Table 1)
. In contrast, the bacterial
lipopolysaccharide (LPS)-induced production of cytokines was
resistant to PT. These results indicated that MMK-1 can modulate the
host defense and immunological response through the G-protein-coupled
receptor FPRL1.
|
DISCUSSION
|
|---|
We show that the synthetic peptide MMK-1, derived from a random
peptide library, was a chemotactic agonist for phagocytic leukocytes by
specifically acting on FPRL1. FPRL1 is cloned by its structure homology
to FPR and binds fMLF with low affinity [5
,
9
, 10
]. This receptor has 69% identity at
the amino acid level to its prototype FPR [5
,
10
]. However, in contrast to FPR, FPRL1 mediates calcium
flux in response to fMLF only when it is stimulated by high
concentrations [14
, 16
], suggesting that
high-affinity agonist(s) for FPRL1 differ from those of FPR. This
hypothesis is supported by recent identification of various agonists
that preferentially bind and activate FPRL1. A peptide domain T21/DP107
derived from HIV-1 envelope protein gp41 can stimulate calcium flux and
chemotaxis through both FPR and FPRL1 but has high selectivity for
FPRL1 [16
]. Two other HIV-1-derived peptides, F pep and
V3 peptide, specifically activate only FPRL1 [17
,
22
]. In addition, a lipid metabolite, LXA4, has been
reported to bind FPRL1 with high affinity and to stimulate GTPase
activity through this receptor [11
]. However, unlike
peptide chemotactic agonists, LXA4 is reported to induce an
anti-inflammatory signaling cascade that inhibits neutrophil
transmigration of epithelial monolayers [23
]. In
contrast to LXA4, an acute-phase protein serum amyloid A which markedly
increases its serum concentration during acute-phase responses and
causes tissue or organ amyloidosis in chronic inflammation
[24
] induces chemotaxis of phagocytic leukocytes through
FPRL1 [12
13
14
]. Therefore, it is possible that FPRL1
transduces, respectively, both anti-inflammatory and proinflammatory
signals in response to lipid agonists versus protein or peptide
agonists [11
, 25
]. In this context, it has
recently been suggested that LXA4 and peptide agonists might use
divergent domains on FPRL1, and glycosylation of the receptor could be
essential for peptide but not for LXA4 signaling. Although FPRL1 was
initially identified in phagocytic leukocytes, recent studies have
detected the expression of this receptor in a great variety of cell
types, including cells of nonhematopoietic origin [26
].
Identification of specific host-derived agonists for FPRL1 suggests an
important role of this receptor in inflammatory responses.
Construction and screening of random peptide libraries have become
important means of identifying biologically active sequences.
Hexapeptide sequence WKYMVm (W peptide) isolated from such a library is
reported to stimulate the activation of phospholipase D
[27
], phosphoinositide hydrolysis, and Ca2+
mobilization in neutrophils and B lymphocytes [28
,
29
]. We recently identified both FPRL1 and FPR as
functional receptors for W peptide [20
]. MMK-1 was also
derived from a random peptide library and was identified by a novel
autocrine selection method in yeasts engineered to express human FPRL1
[15
]. Several peptides have been found to induce calcium
mobilization via interaction with either or both FPRL1 and FPR. MMK-1
was described as a preferential inducer of Ca2+ flux
through FPRL1 [15
]. In our study, we identified this
peptide as a highly specific chemotactic factor for FPRL1-transfected
HEK 293 cells. In addition, MMK-1 potently activated phagocytic
leukocytes and could enhance PT-sensitive production by human monocytes
of proinflammatory cytokines IL-1ß and IL-6, which play an important
role in the host innate defense and immunological responses
[30
]. Although formal proof could be obtained only by
neutralizing anti-FPRL1 antibodies or specific antagonists, which are
not available at the present time, the use of FPRL1 by MMK-1 to
activate human phagocytes was nevertheless suggested by the observation
that MMK-1 signaling in these cells was completely desensitized by
well-defined FPRL1 agonist F pep [17
]. In addition, in
binding studies with 125I-labeled W peptide, which is known
to activate both FPR and FPRL1, MMK-1 effectively competed with W
peptide binding to FPRL1- but not FPR-transfected cells. Furthermore,
we demonstrated a highly efficacious and preferential activation of
mFPRL2 by MMK-1. In fact, among various chemotactic agonists specific
for FPRL1, MMK-1 is one of the most potent [14
,
16
, 20
21
22
] and activates the receptor at
picomolar and low-nanomolar concentrations. This is supported also by
the observation that at equal concentrations, MMK-1 is more effective
in stimulating monocyte release of the proinflammatory cytokines
IL-1ß and IL-6 (Table 2
). Thus, in view of the potential importance of FPRL1 in
inflammatory and immunological responses, MMK-1 can be a very useful
molecule to study the signaling and function of this receptor.
|
ACKNOWLEDGEMENTS
|
|---|
This project was funded in whole or in part with federal
funds from the National Cancer Institute, National Institutes of
Health, under contract no. NO1-CO-56000. The authors thank Dr. R.
Snyderman, Duke University, Durham, NC, for providing ETFR cells, Dr.
J. J. Oppenheim for reviewing the manuscript, and C. Fogle and C.
Holan for secretarial assistance. The content of this publication does
not necessarily reflect the views or policies of the Department of
Health and Human Services, nor does mention of trade names, commercial
products, or organizations imply endorsement by the U.S. government.
The publisher or recipient acknowledges the right of the U.S.
government to retain a nonexclusive, royalty-free license in and to any
copyright covering the article.
Received October 16, 2000;
revised January 9, 2001;
accepted February 26, 2001.
|
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