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*
Laboratory of Molecular Immunoregulation, Division of Basic Sciences;
Intramural Research Support Program, Science Applications International Corporation-Frederick, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD 21702; and
Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
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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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-helical rod-like
oligomer (4, 5). Synthetic analogues of both T21/DP178 and T20/DP178
have been shown to inhibit virus-mediated cell-cell fusion and to
reduce the infectious titer of cell-free virus (5, 6, 7, 8, 9, 10, 11). The
anti-HIV-1 activity of these peptides is presumably due to their
competitive association with the native segments on gp41, thus blocking
the conversion to the fusogenic configuration of the virus. In the course of investigating the basis for HIV-1-associated suppression of monocyte functions, we found that preexposure of human monocytes to either HIV-1 envelope proteins gp120 or gp41 inhibited their chemotactic responses to a wide variety of chemoattractants, including the bacterial chemotactic peptide fMLP and a number of recently defined chemokines, through a mechanism resembling heterologous "desensitization" (12, 13). The inactivation of monocyte chemotactic responses by HIV-1 envelope proteins may be responsible for the reduced migratory response of monocytes from AIDS patients to a variety of chemoattractants in vitro (14). To further define the structural basis for the capacity of HIV-1 envelope proteins to "desensitize" host cells, we evaluated the effects of selected peptide segments of gp41 on human immune cells. We initially found that synthetic C-terminal peptide segment, T20/DP178, was a potent agonist of FPR, a seven-transmembrane, G-protein-coupled receptor on human phagocytic cells used by chemotactic N-formyl peptides (Refs. 15 and 16, and Su et al., manuscript in preparation). This led us to further investigate the effect of synthetic T21/DP107. Here, we report that T21/DP107 activates human monocytes and neutrophils by using two N-formyl peptide receptors (FPR)4, the prototype FPR and its variant FPR-like 1 (FPRL1), and exhibits much higher efficacy on FPRL1.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The T21/DP107 was synthesized and purified by the Department of Biochemistry, Colorado State University (Fort Collins, CO), according to the published sequence (aa 558–595 of gp41) (5): Ac-NNLLRAIEAQQHLLQLTVWGIKQLQARILAVERYLKDQ-NH2. The purity was 90% or more, and the amino acid composition was verified by mass-spectrometer. The endotoxin levels in dissolved peptide were undetectable. The synthetic formyl peptide fMLP was purchased from Sigma (St. Louis, MO). 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 ellutriation to yield >90% purity. 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 FPR (ETFR) were a kind gift of Drs. H. Ali and R. Snyderman (Duke University, Durham, NC). The cells were designated ETFR and were grown in DMEM, 10% FCS, and 0.8 mg/ml geneticin (G418) to maintain selection pressure. The FPRL1 cDNA was cloned and transfected into human embryonic kidney cells 293 (designated FPRL1/293 cells), as reported previously (17). The cells were maintained in DMEM, 10% FCS, and 2 mg/ml geneticin (G418).
Chemotaxis
Leukocyte, ETFR, and FPRL1/293 cell migration was assessed using
a 48-well microchemotaxis chamber technique, as previously described
(18, 19, 20). Different concentrations of stimulants were placed in wells
of the lower compartment of the chamber (Neuro Probe, Cabin John, MA),
and the cell suspension was seeded in 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). For CD3+ T
lymphocytes, the filters were precoated with 20 µg/ml bovine
fibronectin (Sigma). 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 the attachment of the cells.
After incubation at 37°C (90 min for monocytes, 60 min for
neutrophils, 180 min for T cells, and 300 min for ETFR or FPRL1/293
cells), the filters were removed, stained, and the 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 significance of the increase in cell migration
was determined using Student’s t test, and CI 
2 was
statistically significant compared with medium control (at least
p < 0.05).
Calcium mobilization
Calcium mobilization was assayed by incubating 107 cells/ml of monocytes, neutrophils, FPRL1, or ETFR transfectants in loading buffer containing 138 mM NaCl, 6 mM KCl, 1 mM CaCl2, 10 mM HEPES (pH 7.4), 5 mM glucose, and 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).
Unless specified, all experiments were performed at least five times with similar results, and data shown in this study were from representative experiments.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, A and B,
human PBMC and neutrophils migrated in a dose-dependent manner in
response to a concentration gradient of T21/DP107. The chemotactic
activity of T21/DP107 was already significant at nM concentrations for
both monocytes and neutrophils, and the cell response remained high
with only slight reduction when T21/DP107 was used at
10-5-10-4 M (Fig. 1B). In contrast
to phagocytes, human CD3+ T lymphocytes showed a marginally
significant migration (CI = 2) in response to high concentrations
(5 x 10-6 M and higher, Fig. 1B),
indicating the effect of T21/DP107 is mainly on phagocytic cells. We
next examined whether phagocyte migration induced by T21/DP107 was
dependent upon the effect of chemotaxis or chemokinesis. Checkerboard
analyses showed that monocytes migrated when higher concentrations of
T21/DP107 were present in the lower wells of the chemotaxis chamber
(Table I). There was no enhanced cell
migration when higher concentrations of T21/DP107 were present in the
upper wells. With equal concentrations of T21/DP107 in both upper and
lower wells, a slightly increased monocyte migration was observed.
These results suggest that the cell migration induced by T21/DP107 was
due mainly to a chemotactic effect with minor contribution of
chemokinesis. The migration of monocytes and neutrophils to T21/DP107
was completely inhibited by pretreatment of the cells with pertussis
toxin, but not by cholera toxin or herbimycin A (Fig. 1C,
and data not shown), suggesting that a G-protein of the Gi type-coupled
receptor was involved (15, 16, 21, 22, 23, 24). This was supported by the
potent induction of a dose-dependent, and pertussis toxin-sensitive,
calcium (Ca2+) mobilization in monocytes and neutrophils by
T21/DP107 (Fig. 2, A and
C). The Ca2+-mobilizing activity of T21/DP107
was also significant at nM concentrations, indicating that this
synthetic peptide is a potent activator of human phagocytic cells. The
possibility that byproduct(s) formed during peptide
synthesis/purification might account for the activity of T21/DP107 was
unlikely, since a fusion peptide (aa 517–532 of gp41) synthesized
during the same period as T21/DP107 did not posses any chemotactic or
Ca2+-mobilizing activity in phagocytes (data not shown).
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IL-8, and stromal cell-derived factor-1 (data not shown). Therefore,
T21/DP107 does not share a receptor with any of these chemokines.
However, high concentrations (1 µM) of the bacterial chemotactic
N-formylated peptide fMLP had a partial desensitizing effect
on T21/DP107-induced Ca2+ mobilization in both monocytes
and neutrophils (Fig. 2
, B and D). In contrast,
T21/DP107 did not significantly desensitize the effect of fMLP (Fig. 2, B and D). These results suggest that T21/DP107
may share receptor(s) with fMLP on human phagocytic cells and may have
preference on a receptor for which fMLP has lower affinity.
Since fMLP was known to induce Ca2+ in phagocytes through
at least two seven-transmembrane, G-protein-coupled receptors, FPR and
FPRL1 (15, 16, 17), we tested the effect of T21/DP107 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 FPR-transfected
rat basophil leukemia cell line (ETFR cells), with minimal effective
dose at low pM concentration range (Fig. 3A). In contrast, the minimal
effective concentration for fMLP to induce Ca2+
mobilization in FPRL1-transfected cells (FPRL1/293 cells) was at
low µM range (Fig. 3D). These results confirmed the
previous observation that FPR is a high-affinity receptor for fMLP,
whereas FPRL1 has much lower affinity (15, 16, 17). The synthetic T21/DP107
also induced Ca2+ mobilization in cells transfected with
either of these receptors (Fig. 3, B and E).
However, the minimal effective dose for T21/DP107 to activate FPRL1 was
at nM range as compared with low µM range on FPR, suggesting that
T21/DP107 activates FPRL1 with higher efficacy. A comparison for the
efficacy between T21/DP107 and fMLP on two receptors could be better
illustrated by the requirement of the concentrations to elicit an equal
response by these two agents. In FPR-expressing cells, to induce a
change in the ratio of 2 at 340/380 nm wavelength fluorescence,
10-10 fMLP vs 10-5 T21/DP107 were required;
whereas in FPRL1/293 cells, 5 x 10-5 fMLP vs 5
x 10-7 T21/DP107 induced a change in the ratio of 0.6.
Such comparison indeed indicates T21 to be a more potent agonist for
FPRL1 compared with fMLP. This was further supported by results of
cross-desensitization of Ca2+ flux between T21/DP107 and
fMLP in both receptor transfectants. As shown in Fig. 3, C
and F, although sequential stimulation of the cells
expressing FPR or FPRL1 with T21/DP107 and fMLP resulted in
bidirectional desensitization, a 1000-fold excess of fMLP was required
to desensitize the effect of T21/DP107 in FPRL1/293 cells. Conversely,
a much higher concentration of T21/DP107 was necessary to completely
abolish the subsequent response to fMLP of the cells transfected with
FPR. In control experiments, T21/DP107 and fMLP did not induce any
Ca2+ mobilization in parental or mock-transfected rat
basophil cell line and human embryonic kidney 293 cells (data not
shown). These results further support the notion that FPR and its
variant, FPRL1, are differentially activated by fMLP and T21/DP107.
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, A and B), but
these cells failed to migrate in response to a wide range of
concentrations of fMLP (Fig. 4B). In contrast, ETFR cells
were induced to migrate by fMLP at nM range concentrations, but much
higher concentrations of T21/DP178 were required to induce the
migration of the same cells (Fig. 4C). The chemotaxis
experiments indicate that fMLP is only a partial agonist for FPRL1,
since it did not induce FPRL1-expressing cells to migrate. T21/DP107,
on the other hand, appears to be an efficient agonist on both FPR and
FPRL1, although the efficacy for FPR-expressing cells was much lower
than for FPRL1-expressing cells.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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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 (17, 30, 31, 32).
The cloning of the same receptor, termed FPRH2, from a genomic library
was also described (33). FPRL1 possesses 69% identity at the amino
acid level to FPR (15, 16), and both receptors are expressed by
monocytes and neutrophils and are clustered on human chromosome 19q13
(33, 34). While fMLP is a high-affinity agonist for FPR, it interacts
with and induces Ca2+ flux in FPRL1 only at high
concentrations (Fig. 3D, and Refs. 17, 31, and 34). In our
study, fMLP did not induce significant migration of FPRL1/293 cells at
a concentration as high as 50 µM (5 x 10-5 M; Fig. 4B), suggesting that fMLP is not a full agonist for FPRL1.
In contrast, T21/DP107, although also activating both receptors, showed
a much higher efficacy on FPRL1 and induces migration of FPRL1/293
cells at nM concentrations. Thus, compared with fMLP, T21/DP107 is a
functionally more relevant 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 (15).
Recently, the expression of this receptor has been reported to be
highly inducible in epithelial cells by specific cytokines, such as
IL-13 and IFN-
(35). 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) (36), which increases
its concentration by up to several hundred-fold during acute phase
responses and is a potent phagocyte chemoattractant and activator (37, 38). SAA and T21/DP107 attenuated each other’s
Ca2+-mobilizing activity in FPRL1/293 cells, indicating
that these two chemoattractants share FPRL1 as their functional
receptor (Su et al., data not shown). It should be noted that T21/DP107
does not bear any significant sequence homology to either fMLP or
SAA. Therefore, FPRL1, like its prototype FPR, is also capable of
hosting a broad spectrum of ligands. It should be pointed out that in
our study, human CD3+ T lymphocytes showed a weak migration
in response to high concentrations of T21/DP107. Whether this low
level migration is also mediated by the presence of FPRL1 in T
cells is under investigation.
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 termed LXA4R) (39). 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 40). LXA4 was subsequently reported to inhibit neutrophil chemotaxis (41) and transepithelial migration induced by chemotactic agents (42). LXA4 bound to Chinese hamster ovary cells transfected with FPRL1(LXA4R) with high affinity and increased GTPase activity and the release of esterified arachidonate (39). Thus, LXA4 has been proposed to be an endogenously produced ligand for FPRL1 (39, 43). Although LXA4 has not been documented to induce Ca2+ mobilization in neutrophils or FPRL1-transfected cells (39), it was reported to induce Ca2+ flux and chemotaxis in monocytes, presumably through FPRL1 (44, 45). Based on these observations, differential activation of second messengers in monocytes vs neutrophils by LXA4 was postulated. In our study, we did not detect significant induction of Ca2+ flux or chemotaxis in FPRL1/293 cells by a commercially available LXA4 (Biomol, Plymouth Meeting, PA), nor did we observe inhibition of T21/DP107 signaling by this LXA4 in either phagocytes or FPRL1/293 cells. Since LXA4 is a highly unstable lipid metabolite that could rapidly convert to biologically inactive form, we cannot exclude the possibility that the LXA4 we used might have lost its activity during experiments. Further study is needed to better preserve the activity of LXA4 and to compare the interaction of FPRL1 with its protein/peptide ligands, such as T21/DP107, SAA, and fMLP, vs its lipid ligand LXA4 to clarify these results.
Although 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 potent phagocyte migration and activation by its 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 leading to cell adhesion, chemotaxis, release of oxygen intermediates, enhanced phagocytosis, and bacterial killing, as well as mitogen-activated protein kinase activation leading to gene transcription (15, 16). Activation by fMLP can also lead to heterologous desensitization of the subsequent cell response to other G-protein receptor ligands (46, 47), including chemokines. In our previous study, incubation of human phagocytes with FPRL1 agonist SAA resulted in a reduction of cell responses to a number of chemoattractants (38), suggesting that activation of FPRL1 may also activate signaling events that cause desensitization of other G-protein-coupled chemotactic receptors.
The relevance of our current findings to the course of disease effects on host and benefits, if any, to HIV-1 infection remains to be established. However, our observations do suggest some speculation possibilities. It has been reported that monocytes and neutrophils isolated from HIV-1-infected patients responded poorly to a variety of chemoattractants, including fMLP (14, 48, 49, 50, 51) in vitro. We have found that recombinant soluble gp41 of the HIV-1 is able to potently down-regulate the expression and function of fMLP receptor and the receptors for a variety of chemokines on monocytes, including CCR5 and CXCR4, two major HIV-1 fusion cofactors (13). Intriguingly, the effect of gp41 on monocytes is dependent on the presence of cellular CD4, another fusion receptor of HIV-1 (13). It is not clear whether soluble gp41 itself is capable of interacting with FPR or, alternatively, conjugation with CD4 may cause exposure of its domains to interact with these receptors. Also, 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. In a parallel study, we found that synthetic peptide T20/DP178 of the gp41 C-terminal domain was a potent and selective FPR agonist, while its analogues lacking several amino acids were FPR antagonists (Su et al., manuscript in preparation). This, together with the present observation of T21/DP107, suggests that gp41 may possess multiple domains that could potentially interact with cellular receptors, thus affecting the immune responses. It has been reported that gp41 Ag could be detected in brain tissues of AIDS dementia (52), and Abs recognizing various epitopes of gp41 appear at early stages of HIV-1 infection (53). In fact, we found that both synthetic T21/DP107 and T20/DP178 epitopes of gp41 were recognized by sera from AIDS patients by immunoblotting (data not shown), suggesting that gp41 and its epitopes are accessible to host cells, including APCs. Therefore, although 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 an initial stimulation of immune system in the early stage of the disease followed by progressive immunosuppression.
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Acknowledgments |
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Footnotes |
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2 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 right of the U.S. Government to retain a nonexclusive, royalty-free license in and to any copyright covering the article.
3 Address correspondence and reprint requests to Ji Ming Wang, Laboratory of Molecular Immunoregulation, Division of Basic Sciences, National Cancer Institute-Frederick Cancer Research and Development Center, Building 560, Room 31-19, Frederick, MD 21702-1201. E-mail address:
4 Abbreviations used in this paper: FPR, formyl peptide receptor; FPRL1, FPR-like 1; ETFR, epitope-tagged FPR; CI, chemotaxis index; SAA, serum amyloid A.
Received for publication December 10, 1998. Accepted for publication February 17, 1999.
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References |
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and inhibits tumor necrosis factor -induced IL-8 release. J. Exp. Med. 187:1285.This article has been cited by other articles:
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B.-Q. Li, M. A. Wetzel, J. A. Mikovits, E. E. Henderson, T. J. Rogers, W. Gong, Y. Le, F. W. Ruscetti, and J. M. Wang The synthetic peptide WKYMVm attenuates the function of the chemokine receptors CCR5 and CXCR4 through activation of formyl peptide receptor-like 1 Blood, May 15, 2001; 97(10): 2941 - 2947. [Abstract] [Full Text] [PDF]
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R. He, L. Tan, D. D. Browning, J. M. Wang, and R. D. Ye The Synthetic Peptide Trp-Lys-Tyr-Met-Val-D-Met Is a Potent Chemotactic Agonist for Mouse Formyl Peptide Receptor J. Immunol., October 15, 2000; 165(8): 4598 - 4605. [Abstract] [Full Text] [PDF]
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 De Yang, Q. Chen, A. P. Schmidt, G. M. Anderson, J. M. Wang, J. Wooters, J. J. Oppenheim, and O. Chertov Ll-37, the Neutrophil Granule-And Epithelial Cell-Derived Cathelicidin, Utilizes Formyl Peptide Receptor-Like 1 (Fprl1) as a Receptor to Chemoattract Human Peripheral Blood Neutrophils, Monocytes, and T Cells J. Exp. Med., October 2, 2000; 192(7): 1069 - 1074. [Abstract] [Full Text] [PDF]
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D. Yang, Q. Chen, S. Stoll, X. Chen, O. M. Z. Howard, and J. J. Oppenheim Differential Regulation of Responsiveness to fMLP and C5a Upon Dendritic Cell Maturation: Correlation with Receptor Expression J. Immunol., September 1, 2000; 165(5): 2694 - 2702. [Abstract] [Full Text] [PDF]
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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, March 1, 2000; 95(5): 1810 - 1818. [Abstract] [Full Text] [PDF]
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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 J. Immunol., December 15, 1999; 163(12): 6777 - 6784. [Abstract] [Full Text] [PDF]
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J. K. Hartt, G. Barish, P. M. Murphy, and J.-L. Gao N-Formylpeptides Induce Two Distinct Concentration Optima for Mouse Neutrophil Chemotaxis by Differential Interaction with Two N-Formylpeptide Receptor (Fpr) Subtypes: Molecular Characterization of Fpr2, a Second Mouse Neutrophil Fpr J. Exp. Med., September 6, 1999; 190(5): 741 - 748. [Abstract] [Full Text] [PDF]
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J. S. Mills, H. M. Miettinen, D. Cummings, and A. J. Jesaitis Characterization of the Binding Site on the Formyl Peptide Receptor Using Three Receptor Mutants and Analogs of Met-Leu-Phe and Met-Met-Trp-Leu-Leu J. Biol. Chem., December 8, 2000; 275(50): 39012 - 39017. [Abstract] [Full Text] [PDF]
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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 J. Biol. Chem., June 8, 2001; 276(24): 21585 - 21593. [Abstract] [Full Text] [PDF]
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H. L. Tiffany, M. C. Lavigne, Y.-H. Cui, J.-M. Wang, T. L. Leto, J.-L. Gao, and P. M. Murphy Amyloid-beta Induces Chemotaxis and Oxidant Stress by Acting at Formylpeptide Receptor 2, a G Protein-coupled Receptor Expressed in Phagocytes and Brain J. Biol. Chem., June 22, 2001; 276(26): 23645 - 23652. [Abstract] [Full Text] [PDF]
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