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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 94 No. 4 (August 15), 1999:
pp. 1165-1173
A Synthetic Peptide Derived From Human Immunodeficiency Virus Type 1 gp120 Downregulates the Expression and Function of Chemokine Receptors
CCR5 and CXCR4 in Monocytes by Activating the 7-Transmembrane
G-Protein-Coupled Receptor FPRL1/LXA4R
By
Xiyun Deng,
Hirotsugu Ueda,
Shao Bo Su,
Wanghua Gong,
Nancy M. Dunlop,
Ji-Liang Gao,
Philip M. Murphy, and
Ji Ming Wang
From the Laboratory of Molecular Immunoregulation, Division of Basic
Sciences, and the Intramural Research Support Program, SAIC Frederick,
National Cancer Institute-Frederick Cancer Research and Development
Center, Frederick, MD; and the Laboratory of Host Defenses, National
Institute of Allergy and Infectious Diseases, National Institutes of
Health, Bethesda, MD.
 |
ABSTRACT |
Because envelope gp120 of various strains of human immunodeficiency
virus type 1 (HIV-1) downregulates the expression and function of a variety of chemoattractant receptors through a process of
heterologous desensitization, we investigated whether epitopes derived
from gp120 could mimic the effect. A synthetic peptide domain,
designated F peptide, corresponding to amino acid residues 414-434 in
the V4-C4 region of gp120 of the HIV-1 Bru strain, potently reduced
monocyte binding and chemotaxis response to macrophage inflammatory
protein 1 (MIP-1) and stromal cell-derived factor 1
(SDF-1), chemokines that use the receptors CCR5 and
CXCR4, respectively. Further study showed that F peptide by itself is an inducer of chemotaxis and calcium mobilization in human monocytes and neutrophils. In cross-desensitization experiments, among the numerous chemoattractants tested, only the bacterial chemotactic peptide fMLF, when used at high concentrations, partially attenuated calcium mobilization induced by F peptide in phagocytes, suggesting that this peptide domain might share a 7-transmembrane,
G-protein-coupled receptor with fMLF. By using cells transfected with
cDNAs encoding receptors that interact with fMLF, we found that F
peptide uses an fMLF receptor variant, FPRL1, as a functional receptor.
The activation of monocytes by F peptide resulted in downregulation of
the cell surface expression of CCR5 and CXCR4 in a protein kinase
C-dependent manner. These results demonstrate that activation of FPRL1
on human moncytes by a peptide domain derived from HIV-1 gp120 could
lead to desensitization of cell response to other chemoattractants.
This may explain, at least in part, the initial activation of innate
immune responses in HIV-1-infected patients followed by immune suppression.
This is a US government work. There are no restrictions on its use.
| |
INTRODUCTION |
HUMAN IMMUNODEFICIENCY virus type 1 (HIV-1) uses CD4 as the primary receptor and the specific chemokine
receptors as fusion cofactors.1,2 The acquired
immunodeficiency syndrome (AIDS) caused by HIV-1 is characterized by
profound immunosuppression with high incidence of certain neoplasms
and/or opportunistic infections. Although T-lymphocyte dysfunction is
the key feature of AIDS-associated immunosuppression, the function of
monocytes and neutrophils in AIDS patients is also
impaired.3-7 Our previous studies have shown that monocytes
from healthy donors, when preincubated with gp120 of various HIV-1
strains, displayed markedly reduced Ca2+ mobilization and
chemotaxis in response to a number of chemoattractants, including the
bacterial chemotactic peptide fMLF and chemokines accompanied by
receptor downregulation.8 The gp120-induced chemoattractant
receptor downregulation apparently resulted from a heterologous
desensitization that required activation of protein kinase C (PKC) and
was CD4-dependent.8
To define the structural basis for gp120 to attenuate monocyte response
to chemoattractants, a series of synthetic peptide domains derived from
HIV-1 gp120 were tested for their effect on monocyte activation. One of
these synthetic peptide domains, which is designated F peptide and
corresponds to amino acid residues 414-434 in the V4-C4 region of gp120
of the HIV-1 Bru strain, potently reduced monocyte binding and
chemotaxis in response to CC chemokine MIP-1 and CXC chemokine
SDF-1 when used at low micromolar concentrations.
Further study showed that F peptide could by itself induce chemotaxis
and Ca2+ mobilization in human phagocytic cells. Based on
the attenuation of Ca2+ mobilization in phagocytes in
response to F peptide by high concentrations of fMLF, we postulated
that F peptide might share a phagocyte receptor with fMLF. Two
functional receptors, FPR and FPRL1, have been identified for fMLF.
Both receptors belong to the 7-transmembrane, G-protein-coupled
Rhodopsin superfamily.9-11 Whereas FPR has high affinity
for fMLF and is activated by picomolar concentrations of fMLF, FPRL1 is
activated by fMLF at micromolar concentration range and was defined as
a low-affinity receptor for fMLF.9-11 These activation
patterns of fMLF receptors led us to examine whether F peptide was
capable of interacting with the low-affinity fMLF receptor, FPRL1. By
using human kidney embryonic epithelial 293 cells transfected to
express various chemoattractant receptors, we demonstrate that F
peptide uses FPRL1 as its functional receptor. Our study suggested that
this peptide domain derived from HIV-1 gp120 downregulates the
expression and function of chemokine receptors CCR5 and CXCR4 in
monocytes by activating FPRL1-mediated signaling cascade.
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MATERIALS AND METHODS |
Reagents and cells.
F peptide, EGSDTITLPCRIKQFINMWQE, which corresponds to amino acid
residues 414-434 in the V4-C4 region of HIV-1 gp120 (strain Bru), was
purchased from Intracell (Cambridge, MA) and was also synthesized and
purified by the Department of Biochemistry, Colorado State University
(Fort Collins, CO) according to the published sequence. The amino acid
composition was verified by mass spectrometer. The endotoxin levels in
dissolved peptide were undetectable by Limulus amebacyte lysate assays
(sensitivity, 0.06 IU/mL; Bio Whittaker, Walkersville, MD). The
synthetic chemotactic peptide fMLF was purchased from Sigma (St Louis,
MO). Several other synthetic HIV-1 gp120 domains were also purchased
from Intracell and tested for their biological effects. These peptide
domains include V3 region of gp120 MN (RIHIGPGRAFYTTKN), amino acid
120-135 of gp120 Bru (VKLTPLCVSLKCTDLG), amino acid 302-324 of gp120
SBI-IIIB (TRPNNNTRKSIRIQRGPGRAFVT), amino acid 307-320 of gp120 Bru
(NKRKRIHIGPGRAF), and amino acid 460-474 of gp120 Bru
(TRDGGNNNNGSEIFR). Radio-iodinated chemokines were purchased from
DuPont NEN (Boston, MA). Monoclonal anti-CXCR4 (12G5) and anti-CCR5
(2D7) antibodies were obtained from NIH AIDS Research and Reference
Reagent Program (Rockville, MD). Monoclonal anti-CD4 antibody was
purchased from Biogenesis (Poole, UK). Fluorescein isothiocyanate
(FITC)-conjugated antimouse IgG (whole molecule) was
purchased from Sigma.
Human peripheral blood monocytes were isolated from buffy coats (NIH
Clinical Center, Transfusion Medicine Department, Bethesda, MD)
enriched for mononuclear cells by using iso-osmotic Percoll gradient as
previously described.12 Neutrophils were isolated from
buffy coat blood with dextran sedimentation as described.12 The purity of the cell preparations was examined by morphology and was
greater than 90% for monocytes and greater than 98% for neutrophils.
Rat basophilic leukemia cells (RBL-2H3) transfected with epitope-tagged
FPR (designated ETFR) were a kind gift of Drs H. Ali and R. Snyderman
(Duke University, Durham, NC). FPRL1-transfected HEK/293
cells (designated FPRL1/293) were established as previously described.13 All the transfected cells were maintained in
Dulbecco's modified Eagle's medium (DMEM) supplemented
with 10% fetal bovine serum (FBS; Hyclone, Logan, UT), 1 mmol/L
glutamine (GIBCO-BRL, Grand Island, NY) and 800 µg/mL geneticin
(G418; GIBCO-BRL).
Chemotaxis assays.
Chemotaxis assays were performed using 48-well chemotaxis chambers
(Neuro Probe, Cabin John, MD) as described previously.8 Twenty-six to 28 µL of chemoattractants at different concentrations was placed in the wells of the lower compartment of the chamber, and 50 µL of cells (monocytes or neutrophils at 2 × 106/mL and transfected cells at 1 × 106/mL) were placed in the wells of the upper compartment.
The upper and lower compartments were separated by a polycarbonate
filter (Osmonics, Livermore, CA; 5-µm pore size for monocytes and
neutrophils and 10-µm pore size for transfected cells). For migration
of the transfected cells, the filters were precoated with 50 µg/mL
collagen type I as described.14 After incubation at
37°C for different times (90 minutes for monocytes, 60 minutes for
neutrophils, or 5 hours for transfected cells), the filters were
removed and stained and the cells migrated across the filters were
counted under light microscope after coding the samples. The results
were expressed as chemotaxis index (CI), which represents the fold
increase in the number of migrated cells in 3 high-powered fields in
response to chemoattractants over the spontaneous cell migration in
response to control medium.
Binding assays.
Binding assays were performed by preincubating duplicate samples of
human monocytes (2 × 106/sample) with various
concentrations of F peptide for 60 minutes at 37°C in a volume of
200 µL/sample of binding medium (RPMI1640, 1% bovine serum albumin
[BSA], 5 mmol/L HEPES, and 0.05% NaN3). 125I-labeled chemokines (0.12 nmol/L) were then added to
each sample. After incubation for 40 minutes at room temperature, the
cells were washed once with cold phosphate-buffered saline (PBS) and centrifuged through a 10% sucrose/PBS cushion. The tips of each tube
containing cell pellets were cut and the cell-associated radioactivity
was measured in a gamma counter. Unlabeled native chemokines at
1,000-fold excess were used as positive controls to yield nonspecific
binding. Specific binding was obtained by subtraction of nonspecific
binding (in the presence of unlabeled chemokine) from total binding (in
the absence of unlabeled chemokine). The percentage of inhibition of
specific binding by F peptide treatment was calculated as follows: % inhibition = 1  (specific binding on F peptide-treated
cells)/(specific binding on medium-treated cells) × 100%.
Calcium mobilization.
Ca2+ mobilization was measured by incubating
107/mL cells in loading medium (DMEM, 10% FBS, and 2 mmol/L glutamine) with 5 µmol/L Fura-2 AM (Molecular Probes, Eugene,
OR) for 30 minutes at room temperature. The dye-loaded cells were
washed and resuspended in saline buffer (138 mmol/L NaCl, 6 mmol/L KCl,
1 mmol/L CaCl2, 10 mmol/L HEPES [pH 7.4], 5 mmol/L
glucose, and 0.1% BSA) or Hanks' balanced salt solution
(HBSS) at a density of 1 × 106/mL. The
cells were then transferred into quartz cuvettes (1 to 2 × 106 cells in 2 mL) that were placed in a luminescence
spectrometer (LS-50B; Perkin-Elmer, Beaconsfield, UK). Stimulants at
different concentrations were added in a volume of 20 µL to each
cuvette at the indicated time points. The ratio of fluorescence at 340 and 380 nm was calculated using a FL WinLab program (Perkin-Elmer).
Fluorescence-activated cell sorting (FACS) analysis.
Peripheral blood monocytes (0.5 × 106) treated with
medium or F peptide were washed and blocked with 50 µg/mL human IgG
for 15 minutes at 4°C. The cells were then incubated with 5 µg/mL anti-CXCR4 (12G5) or anti-CCR5 (2D7) monoclonal antibody (Courtesy of
NIH AIDS Research and Reagent Program) in ice-cold PBS for 30 minutes.
For PKC inhibitor treatment, the cells suspended in medium were
incubated with 1 ng/mL staurosporine (Kamiya Biomedical Co, Thousand
Oaks, CA) for 10 minutes at 37°C or with 40 ng/mL calphostin C
(Sigma) for 2 hours at 37°C with an 8-W fluorescent light source
located 15 cm away from the samples, followed by incubation with F
peptide and anti-CXCR4 or anti-CCR5 antibody. The cells were then
washed three times with PBS and stained with 1:200 diluted
FITC-conjugated antimouse IgG for 30 minutes at 4°C. After washing,
the cells were fixed in 1% paraformaldehyde and analyzed by a Coulter
flow cytometer (courtesy of Flow Cytometry Laboratory, SAIC Frederick,
NCI-FCRDC, Frederick, MD).
Statistical analysis.
All experiments were performed at least 3 times and the results
presented are from representative experiments. The significance of the
difference between test and control groups was analyzed using the
Student's t-test.
| |
RESULTS |
F peptide inhibits monocyte binding and chemotactic response to
chemokines.
In the first series of experiments, we tested several synthetic gp120
domains available to us, as listed in Materials and Methods, for their
effect on human monocyte activation by chemokines. Only 1 of these
peptide domains, designated F peptide, which is derived from the V4-C4
region (amino acid 414-434) of gp120 of the HIV-1 Bru strain, could
affect the ability of monocytes to bind MIP-1 or SDF-1,
chemokines that use CCR5 and CXCR4 as the functional receptors. When
treated with F peptide at 37°C for 60 minutes, monocytes showed
markedly decreased capacity to bind radiolabeled MIP-1 and SDF-1
(Fig 1). Monocytes preincubated with F
peptide also showed reduced chemotaxis response to both MIP-1 and
SDF-1 (Fig 2), suggesting that the
reduction of chemokine binding on monocytes was associated with
impaired cell function in response to chemokines. In parallel
experiments, monocytes incubated with F peptide also showed reduced
binding and chemotaxis induced by other chemokines such as MIP-1 and
RANTES (data not shown), suggesting that the effect of F peptide on
monocyte activation by chemokines is broad.
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| Fig 1.
Downregulation of iodinated chemokine binding
to monocytes by F peptide. Monocytes were preincubated with F
peptide at the indicated concentrations for 60 minutes at 37°C. The
cells were then incubated with 125I-MIP-1 (A) or
125I-SDF-1 (B) at room temperature for 40 minutes and
pelleted through a sucrose cushion. The cell-associated radioactivity
was determined. Unlabeled MIP-1 or SDF-1 at 1,000-fold excess was
used to define the level of maximal direct competition by native
ligand. The percentage of inhibition of specific chemokine binding is
shown in parentheses. *P < .05 compared with binding to cells
incubated with medium only.
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| Fig 2.
Inhibition of monocyte chemotaxis to chemokines by F
peptide. Monocytes were preincubated with or without F peptide (5 × 10 6 mol/L) for 60 minutes at 37°C and washed 2 times
with PBS. Different concentrations of MIP-1 or SDF-1 were placed
in the lower wells of the chemotaxis chamber. Monocytes were placed in
the upper wells. After incubation for 90 minutes at 37°C, the cells
that migrated across the polycarbonate filter were counted. The
chemotactic activity was expressed as CI. *A significantly reduced
migratory response of F peptide-pretreated monocytes to chemokines
compared with medium-treated cells (P < .05).
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F peptide induces chemotaxis and calcium mobilization in human
phagocytes.
Because a period of preincubation (60 minutes at 37°C) with
monocytes was required for F peptide to downregulate the expression and
function of chemokine binding sites, we asked whether F peptide by
itself might be an activator of phagocytes, thereby desensitizing cell
response to chemokines. As shown in Fig 3A
and B, human neutrophils and monocytes migrated in a dose-dependent
manner in response to F peptide. F peptide induced phagocyte migration
at high nanomolar to low micromolar concentration range, and at 5 × 105 mol/L, the cell response reached maximum
and was comparable to the level induced by an optimal concentration of
fMLF (107 mol/L). Checkerboard analyses showed that
the effect of F peptide on phagocyte migration was chemotactic rather
than chemokinetic, because the cells migrated only in response to
higher concentrations of the F peptide present in the lower wells of
the chemotaxis chamber (Table 1). No
enhanced cell migration was observed in the presence of negative F
peptide concentration gradients (higher concentrations in the upper
wells) or when equal concentrations of the peptide were present in both
upper and lower wells (Table 1). The chemotactic response of both
monocytes and neutrophils to F peptide was not inhibited by treatment
of the cells with PKC inhibitors staurosporine or calphostin C (data
not shown), but was markedly inhibited by pretreatment of the cells
with pertussis toxin (Fig 3C), suggesting that a 7-transmembrane,
G-protein-coupled receptor might be involved in the signaling
triggered by F peptide. This was supported by the observation that F
peptide induced Ca2+ mobilization in both monocytes and
neutrophils at a low micromolar concentration range
(Fig 4A and C), comparable to its
chemotactic activity. We next tested cross-desensitization of calcium
mobilization in monocytes between F peptide and a number of chemokines
of both CXC and CC subfamilies to characterize the putative receptor(s) that mediates F peptide signaling. None of the chemokines tested, including monocyte chemotactic protein 1 (MCP-1), RANTES, MIP-1, interleukin-8 (IL-8), and SDF-1, could desensitize subsequent cell
response to F peptide. F peptide also did not desensitize the
subsequent cell response to these chemokines (data not shown), suggesting that F peptide does not share a receptor with any of these
chemokines. However, the bacterial chemotactic peptide fMLF, when used
at high concentrations (105 mol/L and higher),
attenuated F peptide-induced calcium mobilization in both monocytes and
neutrophils. Conversely, F peptide also partially attenuated the
subsequent cell response to fMLF (Fig 4B and D). These results suggest
that F peptide might use a phagocyte receptor for which fMLF has low
affinity.
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| Fig 3.
Chemotactic activity of F peptide for monocytes and
neutrophils. Different concentrations of F peptide were placed in the
lower wells of the chemotaxis chamber. Monocytes or neutrophils were
placed in the upper wells. After incubation at 37°C, the cells that
migrated across the polycarbonate filter were counted and photographed.
(A) Visualization (original magnification × 400) of neutrophil (upper
panels) and monocyte (lower panels) migration in response to control
medium (Medium), F peptide (F pep; 5 × 105 mol/L), and
fMLF (fMLP; fMLP 107 mol/L). Solid arrows in the figure
denote cells migrated across the filters. An open arrow in the
upper-left panel indicates one of the micropores in the filter. (B)
Fold increase (chemotaxis index) of phagocyte migration in response to
F peptide over control medium. *P < .01 compared with
spontaneous migration. (C) Inhibition of monocyte migration in response
to F peptide by pertussis toxin. Cells preincubated with 100 ng/mL
pertussis toxin (PT) at 37°C for 30 minutes were washed and
examined for migration induced by different concentrations of F
peptide. Cholera toxin (CT) at 100 ng/mL had no effect on monocyte
migration induced by F peptide. *P < .01 compared with
migration of cells incubated with medium alone.
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| Fig 4.
Calcium mobilization induced by F peptide in phagocytes
and attenuation by fMLF. Monocytes (A) or neutrophils (C) were loaded
with Fura-2 and stimulated with different concentrations of F peptide.
The ratio of fluorescence at 340 and 380 nm was recorded and calculated
with the FLWinLab program. (B) and (D) show sequential stimulation of
monocytes (B) or neutrophils (D) with fMLF and F peptide or vice
versa.
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F peptide uses FPRL1 as a functional receptor.
Two receptors that interact with fMLF have been
identified.9-11 The prototype 7-transmembrane,
G-protein-coupled receptor FPR binds and is activated by low nanomolar
concentrations of fMLF and was thus defined as a high-affinity fMLF
receptor. An FPR variant, FPRL1, mediates calcium mobilization by high
concentrations (micromolar range) of fMLF, thus exhibiting a
low-affinity interaction with fMLF.9-11 We then tested the
signaling of F peptide on cells transfected with cDNAs coding either
for FPR or FPRL1. FPRL1/293 cells, but not cells transfected with FPR
(not shown), and chemokine receptors CCR5 or CXCR4 were responsive to F
peptide in both chemotaxis (Fig 5A through
C) and Ca2+ mobilization experiments
(Fig 6). Parental 293 cells also did not
respond to F peptide in both chemotaxis and Ca2+
mobilization assays (not shown). In addition, whereas the
Ca2+ mobilization induced by F peptide in FPRL1/293 cells
was attenuated by high concentrations of fMLF, F peptide conversely
attenuated fMLF-induced Ca2+ mobilization in these cells
(Fig 6B). The concentrations of F peptide required to activate
FPRL1/293 cells were in the low micromolar range, comparable to those
for phagocyte activation. In contrast, F peptide had no effect on
Ca2+ flux induced in CCR5/293 or CXCR4/293 cells by their
respective chemokine ligands RANTES (Fig 6C) or SDF-1 (Fig 6D).
These results indicate that F peptide indeed uses FPRL1 as a functional
receptor.
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| Fig 5.
Chemotactic activity of F peptide for FPRL1/293 cells.
Different concentrations of F peptide were placed in the lower wells of
the chemotaxis chamber. FPRL1/293 cells were placed in the upper wells.
After incubation for 5 hours at 37°C, the cells that migrated
across the polycarbonate filter were counted and photographed. (A)
Visualization (original magnification × 200) of FPRL1/293 cell
migration in response to control medium (Medium; left panel) or F
peptide (F pep; 5 × 105 M; right panel).
Solid arrows in the figure denote cells migrated across the filters. An
open arrow in the left panel indicates one of the micropores in the
filter. (B) Fold increase (chemotaxis index) of FRPL1/293 cell
migration in response to F peptide over control medium. (C) Lack of
chemotactic activity of F peptide for 293 cells transfected to express
CCR5 or CXCR4. MIP-1 and SDF-1 at 10 ng/mL were used as positive
controls. *P < .01 compared with spontaneous migration.
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| Fig 6.
Calcium mobilization induced by F peptide in
FPRL1/293 cells and attenuation by fMLF. FPRL1/293 cells were loaded
with Fura-2 and stimulated with different concentrations of F peptide
(A), and the ratio of fluorescence at 340 and 380 nm was recorded and
calculated. (B) shows sequential stimulation of FPRL1/293 cells with F
peptide and fMLF or vice versa. F peptide (5 × 106
mol/L) did not induce calcium flux in 293 cells transfected with CCR5
(C) or CXCR4 (D) and neither did F peptide (5 × 106
mol/L) attenuate the calcium flux induced by RANTES (200 ng/mL) or
SDF-1 (200 ng/mL) in these cells.
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F peptide downregulates expression of CCR5 and CXCR4 on monocytes.
We next used FACS analysis to investigate whether activation of
monocytes by F peptide through FPRL1 could result in downregulation from cell surface of chemokine receptors. As shown in
Tables 2 and 3,
monocytes preincubated with F peptide showed markedly reduced CCR5 and
CXCR4 expression on the cell surface. The reduction of CCR5 and CXCR4
staining on monocyte cell surface involved activation of PKC, because
monocytes pretreated with PKC inhibitors staurosporine and calphostin C
maintained CCR5 and CXCR4 expression despite incubation with F peptide.
As expected, MIP-1 and SDF-1 competitively inhibited the staining
of CCR5 and CXCR4 on monocytes by their respective antibodies. These
observations suggest that binding of F peptide to FPRL1 on monocytes
activates intracellular PKC, which, in turn, downregulates the
expression and function of the chemokine receptors. Thus, the action of
F peptide on CCR5 and CXCR4 resembles the mechanism of receptor
heterologous desensitization in which PKC is believed to play an
important role.15 In contrast, the reduction of CCR5 or
CXCR4 staining on monocytes by their native ligands did not require the
activation of PKC, because the expression of CCR5 or CXCR4 on monocytes
preincubated with staurosporine or calphostin C was equally
downregulated by MIP-1 or SDF-1 (Tables 1 and 2).
| |
DISCUSSION |
In this study, we report that a peptide domain derived from the V4-C4
region of HIV-1 gp120 was capable of downregulating chemokine receptors
CCR5 and CXCR4 on human monocytes. We further observed that this
peptide domain of gp120 by itself is a potent chemoattractant for both
human monocytes and neutrophils by activating a 7-transmembrane
G-protein-coupled receptor FPRL1, which is a low-affinity receptor for
the bacterial chemotactic peptide fMLF.9-11 The interaction
of FPRL1 in monocytes with F peptide initiates a pertussis
toxin-sensitive G-protein signaling cascade involving the activation of
PKC, which may be responsible for the inhibitory effect of F peptide on
monocyte expression and function of chemokine receptors CCR5 and CXCR4.
Despite being essential fusion coreceptors for HIV-1 and mediating
migration, the full spectrum of the role of CCR5 and CXCR4 in immune
responses remains to be elucidated. However, although CCR5-depleted
mice developed normally, they showed significantly reduced clearance of
Listeria infection, suggesting a defect in monocyte/macrophage
function.16 On the other hand, CXCR4/ mice
had severely reduced B lymphopoiesis, reduced myelopoiesis in fetal
liver, and absence of myelopoiesis in bone marrow.17,18
These results indicate that both CCR5 and CXCR4 are important in
maintaining the homeostasis of the immune system. Therefore, modulation
of the expression and function of these receptors may have signifcant
impact on the host defense against infection and inflammation.
Leukocyte infiltration at the sites of inflammation in vivo is
considered to be based on migration of cells toward a gradient of
chemoattractant(s), either derived from microorganisms or the local
tissue. The discovery of synthetic N-formyl oligopeptide chemoattractants for phagocytes represented a major advance in the
study of leukocyte locomotion.19 Several natural N-formyl peptide chemoattractants, including the prototype N-formyl peptide, fMLF, have since been purified from bacterial supernatants, providing evidence in support of them being biologically relevant ligands for
formyl peptide receptors on phagocytic cells. The prototype receptor
for formyl peptides designated FPR was shown to have a broad spectrum
of agonists, including N-formylated, N-acetylated, N-urea-substituted,
or carbonate-modified peptides.20,21 Structural analysis of
FPR suggests that the binding pocket of this receptor is able to
accommodate an amino terminal group larger than a formyl group,20,21 and this may explain the capacity of this
receptor to interact with a great variety of ligands.
The FPR variant, FPRL1, was identified and molecularly cloned from
human phagocytic cells by low stringency hybridization of the cDNA
library with the FPR sequence and was initially defined as an orphan
receptor.13,22-24 The cloning of the same receptor termed
FPRH2 from a genomic library was also described.25 FPRL1 possesses 69% identity at the amino acid level to FPR,9-11
and both receptors are expressed by monocytes and neutrophils and are
clustered on human chromosome 19q13.25,26 Although fMLF is
a high-affinity agonist for FPR, it interacts with and induces Ca2+ flux in FPRL1 only at high
concentrations.13,25,26 In our study, fMLF did not induce
significant migration of FPRL1/293 cells at a concentration as high as
50 µmol/L (data not shown), suggesting that fMLF is not a fully
functional agonist for FPRL1. In contrast, F peptide induces migration
of FPRL1/293 cells at low micromolar concentrations. Thus, compared
with fMLF, F peptide is a more potent and efficacious agonist for
FPRL1. Although FPRL1 is mainly expressed in monocytes and neutrophils,
cells other than phagocytes, such as hepatocytes, have also been shown
to express FPRL1.9 Recently, the expression of this
receptor has been reported to be highly inducible in epithelial cells
by specific cytokines such as IL-13 and interferon- .27
Therefore, FPRL1 may play an important role in inflammatory and
immunological responses in human cells. In support of this notion, we
recently identified FPRL1 to be a functional receptor for a normal
serum protein, serum amyloid A (SAA),28 which increases its
concentration by up to several hundred-fold during acute-phase
responses and is a potent phagocyte chemoattractant and
activator.29,30 SAA, similar to F petide, specifically
induced Ca2+ flux and chemotaxis of FPRL1/293
cells28 and desensitized the cell response to F peptide and
vice versa (data not shown), indicating that these 2 stimulants indeed
share FPRL1 as a functional receptor. It should be noted that F peptide
does not bear any significant sequence homology to either fMLF or SAA.
Therefore, FPRL1, like its prototype FPR, also is capable of hosting a
broad spectrum of agonists.
Although FPRL1 can be activated by protein or peptide agonists, a lipid
metabolite LXA4 was also reported to be a potent agonist for
FPRL1.31 LXA4 is an eicosanoid generated during multiple cellular events such as inflammation, thrombosis, and atherosclerosis and was initially reported as an anti-inflammatory agent.32 LXA4 binds to FPRL1 (or otherwise termed LXA4R) transfected CHO cells
with high affinity and activates G proteins in these
cells.31 In neutrophils, LXA4 inhibits cell migration in
response to fMLP or leukotriene B4 through epithelial cell
monolayers.33,34 However, in monocytic cells, LXA4 induces
potent calcium mobilization and chemotaxis.35,36 Therefore,
the signaling cascade induced by LXA4 in monocytes versus neutrophils
seems divergent and a further structure-functional study is necessary
to delineate similarities and differences in the interaction of FPRL1
with lipid agonist(s) versus protein/peptide agonists.
The signal transduction pathways mediated by FPRL1 have not been
extensively studied. The high level of homology to FPR, sensitivity to
pertussis toxin, and mediation of cell migration and activation suggest
that FPRL1 and FPR may share some signal transduction events after
interaction with agonists. The binding of FPR by agonists results in a
G-protein-mediated signaling cascade leading to calcium mobilization,
cell adhesion, chemotaxis, release of oxygen intermediates, enhanced
phagocytosis, and bacterial killing, as well as MAP kinase activation
and gene transcription.9-11 Activation by fMLF can also
lead to heterologous desensitization of the subsequent cell response to
other G-protein-coupled receptor ligands, including chemokines.37,38 In our study, F peptide, although being an agonist for FPRL1, downregulates the surface expression and function of
chemokine receptors on monocytes. This effect of F peptide requires
preincubation with monocytes at 37°C for 1 hour and is sensitive to
PKC inhibitors staurosporine and calphostin C, suggesting a similar
mechanism of receptor heterologous desensitization. Because human
phagocytic leukocytes express a number of 7-transmembrane, G-protein-coupled receptors that can be activated by a great array of
chemoattractants, heterologous desensitization of some of the receptors
during pathological states may serve to prevent the overactivation of
the cells by multiple stimulants.
Although F peptide is derived from the sequence of HIV-1 envelope
gp120, the relevance of our current findings to HIV-1 pathogenesis, if
any, remains to be established. However, our observations may suggest
some speculative possibilities. It has been reported that monocytes and
neutrophils isolated from HIV-1-infected patients responded poorly in
vitro to a variety of chemoattractants, including fMLF.3,7
We have found that recombinant soluble gp120 of HIV-1 is able to
downregulate the expression and function of the receptors for a variety
of chemokines on monocytes, including CCR5 and CXCR4, 2 major HIV-1
fusion cofactors.8 The expression of receptors for
chemokine IL-8 on neutrophils of HIV-1-infected patients was also
downregulated.6 In addition, soluble gp120 was able to
downregulate the surface expression of the receptors for fMLF and
complement component C5a in normal human monocytes.39
The effect of gp120 on monocytes requires the presence of CD4 molecules
and is dependent on a PKC-mediated heterologous chemoattractant receptor desensitization.8 It is not clear whether soluble gp120 itself at higher concentrations (in the micromolar range) is
capable of interacting with formyl peptide receptors or, alternatively, conjugation with CD4 may cause exposure of its domains to interact with
these receptors. Also, because in this study high nanomolar to low
micromolar concentrations of F peptide are needed to activate phagocytes, further study is needed to examine whether HIV-1 envelope proteins undergo proteolytic cleavage in vivo to yield peptide fragments that interact with FPR and/or FPRL1. Nevertheless, it has
been estimated that a concentration of HIV-1 envelope protein per virus
particle could be equal to 1,300 µmol/L.40 Therefore, at
local infection sites, the concentration of HIV-1 envelope and possibly
their peptide segments could be present at a high level. In another
study, we found that a synthetic peptide domain of HIV-1 envelope gp41,
T20/DP178, which exhibits potent anti-HIV-1 activity both in vitro and
in vivo, is a selective agonist of the prototype fMLF receptor
FPR.41 This, together with the present observation with F
peptide, suggests that HIV-1 envelope contains multiple domains that
may potentially interact with cellular receptors, thus affecting the
immune responses. Although the accessibility of such HIV-1 envelope
domain(s) in vivo to host immune cells remains to be determined, it has
been reported that antibodies recognizing various epitopes of gp120
appear at early stages of HIV-1 infection.42 Therefore,
whereas the receptors for formylated peptides such as FPR and FPRL1 are
not used by HIV-1 for fusion, they may participate in the regulation of
host innate immune responses seen in AIDS patients characterized by a
stimulation of immune system in the early stage of the disease followed
by progressive immunosuppression. Further study is currently going on
to clarify the signaling events involved in F peptide-induced CCR5 or
CXCR4 desensitization by using cell lines cotransfected to express
these receptors. In addition, the impact of FPRL1 activation on the capacity of CCR5 and CXCR4 to act as HIV-1 fusion coreceptors is also
of great interest. These studies may provide a novel approach to the
development of anti-inflammation and anti-HIV-1 agents.
| |
ACKNOWLEDGMENT |
The authors thank J.J. Oppenheim for his critical review of this
manuscript, and O.M.Z. Howard, R. Salcedo, W. Shen, D. Yang, H. Dong,
S. Strobl, L. Finch, C. Maloney, and R. Turner for technical assistance. The clerical assistance by C. Fogle is gratefully acknowledged.
| |
FOOTNOTES |
Submitted February 25, 1999; accepted April 19, 1999.
Supported in whole or in part with Federal funds from the National
Cancer Institute, National Institutes of Health, under Contract No.
NO1-CO-56000.
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 US Government. The publisher or
recipient acknowledges right of the US Government to retain a
nonexclusive, royalty-free license in and to any copyright covering
this article.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Ji Ming Wang, MD, Laboratory
of Molecular Immunoregulation, Division of Basic Sciences, National
Cancer Institute-Frederick Cancer Research and Development Center, Bldg
560, Room 31-40, Frederick, MD 21702-1201; e-mail:
wangji{at}mail.ncifcrf.gov.
| |
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N. Chiang, I. M. Fierro, K. Gronert, and C. N. Serhan
Activation of Lipoxin a4 Receptors by Aspirin-Triggered Lipoxins and Select Peptides Evokes Ligand-Specific Responses in Inflammation
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[Abstract]
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C. Dahlgren, T. Christophe, F. Boulay, P. N. Madianos, M. J. Rabiet, and A. Karlsson
The synthetic chemoattractant Trp-Lys-Tyr-Met-Val-DMet activates neutrophils preferentially through the lipoxin A4 receptor
Blood,
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[Abstract]
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Y. Le, W. Gong, B. Li, N. M. Dunlop, W. Shen, S. B. Su, R. D. Ye, and J. M. Wang
Utilization of Two Seven-Transmembrane, G Protein-Coupled Receptors, Formyl Peptide Receptor-Like 1 and Formyl Peptide Receptor, by the Synthetic Hexapeptide WKYMVm for Human Phagocyte Activation
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[Abstract]
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T. Christophe, A. Karlsson, C. Dugave, M.-J. Rabiet, F. Boulay, and C. Dahlgren
The Synthetic Peptide Trp-Lys-Tyr-Met-Val-Met-NH2 Specifically Activates Neutrophils through FPRL1/Lipoxin A4 Receptors and Is an Agonist for the Orphan Monocyte-expressed Chemoattractant Receptor FPRL2
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[Abstract]
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Y. Le, W. Gong, H. L. Tiffany, A. Tumanov, S. Nedospasov, W. Shen, N. M. Dunlop, J.-L. Gao, P. M. Murphy, J. J. Oppenheim, et al.
Amyloid {beta}42 Activates a G-Protein-Coupled Chemoattractant Receptor, FPR-Like-1
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[Abstract]
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ABSTRACT
INTRODUCTION