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Center for Molecular Biology of Inflammation, Institute for Medical Biochemistry, Münster, Germany
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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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Although the FPR was defined initially on granulocytes and macrophages and its action was thought to be confined to the above-mentioned host defense, the immunocytochemical identification of FPR in liver cells, neuronal, and lung tissue suggested additional functions of the receptor possibly elicited by (an) endogenous ligand(s) (2, 3). Such an endogenous ligand has been identified recently, strongly supporting the view of a broader physiological role of the receptor. It is the glucocorticoid-regulated protein annexin 1 (lipocortin 1), which upon interaction with the FPR on human granulocytes desensitizes the cells toward a subsequent fMLP challenge. Moreover, annexin 1 given at higher concentrations can fully activate granulocytes, thus suggesting that the protein participates in modulating inflammatory processes through its interaction with FPR (4).
Annexin 1, a member of the annexin multigene family (5), had previously received considerable attention as an antiinflammatory agent. Among other things, exogenously applied annexin 1 protein as well as peptides derived from its unique N-terminal region inhibit inflammatory responses in different animal models, e.g., by inhibiting neutrophil extravasation (6, 7, 8). Most likely this inhibition is due to an interaction with the FPR on neutrophils, as the N-terminal annexin 1 peptides display the same antimigratory effect in an in vitro model for neutrophil extravasation that can be abrogated by fMLP antagonists (4). Moreover, FPR antagonists block the antimigratory effects of annexin 1 peptides in a mouse peritonitis model, and the dose-dependent inhibition of granulocyte extravasation into inflamed peritoneum produced by annexin 1 peptides is diminished in FPR knockout mice (9).
The finding that the FPR is expressed in nonhemopoietic cells and the identification of a new endogenous ligand (annexin 1) point toward additional functions of the receptor that are mediated by annexin 1. To identify such additional roles, we chose the human lung cell line A549 as a model for acute-phase responses and analyzed whether the FPR is expressed in these cells and could participate in the regulation of such acute-phase proteins. The results obtained reveal for the first time that the FPR can be triggered by an endogenous ligand in nonmyeloid cells and that this activation modulates acute-phase protein expression.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The human adenocarcinoma cell line A549 (obtained from the German Cell Culture Collection, DSMZ, Braunschweig, Germany) was maintained in continuous log-phase growth in DMEM supplemented with 10% FCS, glutamine, and penicillin/streptomycin. Cells were cultured at 37°C in a humidified atmosphere with 7% CO2.
RNA extraction
Confluent A549 and HepG2 cells (
1.5 x
106 cells) were scraped off the culture dishes
and washed twice with PBS at 4°C. Total RNA was then extracted
following a modified phenol/guanidinium thiocyanate isolation procedure
(10). Briefly, the cell pellet was lysed on ice directly
in 0.5 ml 4 M guanidinium thiocyanate, 0.1 M 2-ME, 0.5% sodium
sarcosylate solution in phenol saturated with 0.1 M sodium acetate, pH
4.0. After lysis, 1/5 vol chloroform was added, the solution was
thoroughly mixed, and the resulting organic and aqueous phases were
separated by centrifugation. The aqueous layer was recovered, the RNA
was precipitated with an equal volume of 2-propanol, and the
precipitate was washed with 70% ethanol at 4°C. The pellet was dryed
in a speed-vac centrifuge and dissolved in 0.2 ml 0.1% diethyl
pyrocarbonate-treated water.
Reverse-transcription PCR
Total RNA (3–5 µg) was subjected to reverse transcription using the Super Script II Reverse Transcriptase and reaction conditions specified by the manufacturer (Life Technologies, Karlsruhe, Germany). Reactions were primed with 100 pM random hexamer and 20 pM fMLP receptor-specific 3' oligonucleotide primer (5'-CCTAAAATAAGCAGGAAATGCCTGT-3'), and DNA was then amplified in two rounds of PCR. First round amplification was performed using 1- and 5-µl aliquots of the reverse-transcription reactions, and the oligonucleotide 5'-GACCTAGAACTACCCAGAGCAA-3' as sense and the reverse-transcription 3'-oligonucleotide as antisense primer. PCR was 40 cycles of denaturation at 94°C for 45 s, annealing at 58°C for 1 min, and extension at 72°C for 1 min. Reaction mixtures contained a total volume of 25 µl 50 mM Tris.Cl, pH 9.5, 20 mM (NH4)2SO4, 1 mM DTT, 0.005% Nonidet P-40, 1.5 mM MgCl2, 0.5 M betaine, 5% DMSO, 20 pM each primer, 600 µM dNTP, and 1.25 U Taq polymerase produced and purified as previously described (11). Aliquots of the first PCR were used in a second amplification round with nested oligonucleotide primers, 5'-ATGGAGACAAATTCCTCTCT-3' and 5'-TCACTTTGCCTGTAACTC-3', applying the same reaction and cycling conditions as for the first round, only annealing was at 50°C. Reaction products were resolved in ethidium bromide-stained 1% agarose gels.
Molecular cloning and sequencing
Second round PCR amplicons of the expected length of 1 kb were
gel purified and cloned into a linearized PCR II-TOPO vector, and
cloning was performed following the manufacturer’s protocols (TOPO TA
Cloning kit; Invitrogen, San Diego, CA). Clones were blue/white
selected on X-gal/isopropyl 
-D-thiogalactoside
Luria-Bertani-agar plates, and recombinant clones were confirmed
through PCR screening and EcoRI digestion. Plasmid DNA from
insert-containing clones was obtained from 3-ml overnight cultures and
sequenced using the M13 universal forward and reverse primers and the
Applied Biosystems (Foster City, CA) Big Dye Terminator Cycle
Sequencing Ready Reaction kit. Reaction products were analyzed on an
Applied Biosystems 373A automated sequencer. Sequences obtained were
compared with the published fMLP-R26 sequence using the GENESTREAM
global alignment tool.
Receptor-binding assays
Receptor-binding assays using the fMLP analog
formylNLe-Leu-Phe-NLe-Tyr-Lys (Sigma-Aldrich, Deisenhofen, Germany) was
conducted according to McCoy et al. (3). Briefly, the
peptide was labeled with Na125I and chloramine T
and used at a specific radioactivity of 0.28 mCi/nMol. Confluent
monolayers of A549 cells (106 cells) were
washed with PBS and then incubated at 4°C for 2 h in binding
medium (DMEM, 20 mM HEPES, pH 7.4, 1 mg/ml BSA, 0.05% Tween 20)
containing 125I-labeled fMLP analog and
increasing concentrations of unlabeled peptide. Subsequently, cells
were washed three times with cold PBS and then solubilized in 1 N NaOH
for gamma counting. Binding of radioactive peptide obtained in the
presence of a 10,000-fold molar excess of unlabeled fMLP analog
(typically 1000 cpm/106 cells) was considered
nonspecific and subtracted from the actual cpm values.
Stimulation of A549 cells and quantification of cellular annexin 1 levels
Cells seeded on six-well plates were treated with 10 ng/ml human rIL-6, 100 nM fMLP (Sigma-Aldrich), or 100 µM annexin 1 N-terminal peptide Ac1–26 (N-acetyl-AMVSEFLKQAWFIENEEQEYVQTVKSC; purchased from Interactiva, Ulm, Germany) for 20 h in supplemented DMEM without FCS. Cells were then detached by trypsinization and solubilized with lysis buffer (20 mM HEPES, pH 7.4, 150 mM NaCl, 1 mM EDTA, 0.5% Triton X-100, 0.1% NaDOC, 0.1% SDS) in the presence of PMSF (1 mM), benzamidine (1 mM), aprotinin, leupeptin, and pepstatin (2 µg/ml each). The resulting lysates were centrifuged at 12,000 x g for 5 min at 4°C, and protein concentrations of the supernatants were determined using the bicinchoninic acid assay (Pierce, Rockford, IL) with BSA as a standard.
Equal amounts of protein of the total cellular lysates were subjected to SDS-PAGE and electrophoretically transferred to polyvinylidene difluoride membranes. Membranes were blocked with 5% nonfat dried milk powder for 1 h and then incubated with a mouse mAb directed against annexin 1 (Dianova, Hamburg, Germany), followed by anti-mouse HRP-conjugated secondary Abs for 1 h each. Signal detection was performed with ECL (Amersham Pharmacia Biotech, Freiburg, Germany), according to the manufacturer’s instructions. Signal intensities of the annexin 1 immune-reactive bands were calculated using a Boehringer Mannheim (Mannheim, Germany) Lumi-Imager. The blot shown is a typical result of four experiments.
Indirect immunofluorescence staining and quantification
Actin. Cells grown on coverslips were serum starved for 20 h and then stimulated with varying concentrations of FPR agonist (fMLP at 10–100 nM) to establish conditions revealing an optimal activation of the F-actin increase. For the experiments shown, the optimal peptide concentrations chosen were 100 nM fMLP and 100 µM annexin 1 N-terminal peptide Ac1–26. The peptides were incubated with the serum-starved cells for the indicated period of time, and the cells were then fixed for 4 min in -20°C methanol and stained for F-actin with rhodamine-phalloidin. The cells were then washed extensively in PBS and mounted using mowiol containing 4% n-propylgallat. Images were acquired with a cooled charge-coupled device camera. In each experimental setup, five microscopic fields were selected at random, and the mean fluorescence intensities were quantified using the Metamorph software (Visitron, München, Germany). To assess whether the effects observed are due to direct agonist interaction with the FPR, experiments were also performed in the presence of 20 µM FPR antagonistic peptide Boc1 (N-t-butoxycarbonyl-Met-Leu-Phe; Sigma-Aldrich).
Fibrinogen. Cells were grown on glass coverslips and serum starved for 20 h. Following stimulation with 100 nM fMLP or 100 µM annexin 1 N-terminal peptide Ac1–26 for 20 h, cells were fixed in 4% paraformaldehyde in PBS for 15 min on ice and then permeabilized with 0.2% Triton X-100 in PBS for 1 min. After washing with PBS, the cells were blocked with 2% BSA in PBS for 1 h before staining with rabbit IgGs directed against human fibrinogen (DAKO Diagnostika, Hamburg, Germany). The IgGs were pretreated by preadsorption using nonstimulated cells. Cy2-conjugated goat anti-rabbit IgGs were used as secondary Abs. The cells were washed extensively in PBS and mounted using mowiol containing 4% n-propylgallat.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A link between the FPR and acute-phase responses had been
suggested in previous studies analyzing acute-phase gene expression in
HepG2 hepatoma cells (3). Moreover, an acute-phase
protein, human serum amyloid A, was identified recently as a ligand for
a homologous variant of the FPR, the FPR-like receptor 1, providing
further evidence for a possible involvement of FPR and FPR-like
molecules in the regulation of acute-phase processes (12).
To analyze more directly a connection between FPR and acute-phase
responses and thus provide evidence for a more widespread function of
the FPR, we chose human A549 cells as a model system. These cells of
human alveolar epithelial origin are considered to represent a model of
normal lung cells and had been shown previously to respond with
increased expression of acute-phase proteins to the proinflammatory
agents (13, 14). By RT-PCR on total A549 RNA, we could
generate a single PCR product of 1 kb using nested primers derived from
the sequence of published human FPR. The PCR product was cloned and
sequenced. Sequences obtained were found to correspond to that of the
published human FPR from cells of myeloid lineage (accession number
M60627, not shown). Next, we used receptor-binding assays using the
high affinity fMLP analog formylNLe-Leu-Phe-Nle-Tyr-Lys to analyze
whether the FPR is expressed on the surface of A549 cells. Experiments
were conducted with adherent cells and revealed specific binding that
is inhibited by unlabeled fMLP in a concentration-dependent manner
(Fig. 1
). Scatchard analysis of the
binding data predicts an estimated Kd
of 0.08 nM and a receptor density of 1200 molecules/cell. Although
this number is considerably lower than the receptor density on human
neutrophils, it is in the range of the receptor numbers reported for
HepG2 (6000) and U 87 cells (500) (3, 15).
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The ability of the FPR agonist fMLP to induce actin polymerization
is a well-known short-term effect in neutrophils. Therefore, to
determine whether the FPR is functionally active in A549 cells, we
examined the effect of fMLP on the F-actin content in these cells.
Moreover, we analyzed whether the endogenous FPR ligand, the annexin 1
peptide Ac1–26, would also be capable of triggering responses in A549
cells. The kinetics and magnitudes of changes in the F-actin content in
cells treated with fMLP or Ac1–26 are shown in Table I. Both FPR ligands caused a rapid (less
than 1 min) and significant increase that subsequently declined toward
the basal level. After 15 min, the F-actin content even decreased
further to 80% when compared with buffer-treated control cells.
Interestingly, the Ac1–26 peptide triggered a slightly more pronounced
increase in F-actin than the fMLP peptide used at
103-fold lower concentration. In contrast, when
applied at the same relative concentrations, fMLP is more active than
the Ac1–26 peptide in inducing neutrophil responses (4).
To elucidate whether the increases in F-actin content are direct
effects elicited by the peptides applied or due to an intermediate
produced, we specifically neutralized the agonistic peptides. Because
no good neutralizing Abs are available, we decided to use well-known
fMLP antagonists previously shown to also block the effect of the
N-terminal annexin 1 peptide (4). Inclusion of the Boc1
antagonist completely abolished the fMLP-induced increase in F-actin,
indicating that this response is triggered specifically by the
agonistic peptides (not shown).
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Activation of the FPR by the bacterial ligand fMLP has been linked
to the regulation of acute-phase protein biosynthesis (3).
Given the finding that the FPR is present and active in A549 cells, we
next examined the possibility that stimulation of the FPR through fMLP
or the novel endogenous ligand Ac1–26 is able to induce changes in the
expression of acute-phase proteins in these cells. We selected
fibrinogen as prototype for a positive acute-phase protein because
fibrinogen is up-regulated both in HepG2 and A549 cells by IL-6
(16). A549 cells were incubated for 20 h in
serum-free medium containing fMLP, the annexin 1 peptide Ac1–26, or
IL-6, respectively, with the latter included as a positive control. The
fibrinogen content was then visualized by staining with anti-human
fibrinogen IgGs. Control, i.e., nontreated, cells revealed virtually no
staining (Fig. 2A), whereas
treatment with IL-6 led to a drastic increase in the fibrinogen signal,
which reflects itself as a punctate staining and a faint network
pattern (Fig. 2B). Importantly, treatment with both fMLP
(Fig. 2D) and Ac1–26 (Fig. 2C) resulted in a
clearly increased fibrinogen staining indicative of an elevation of
fibrinogen expression. The staining pattern is consistent with that of
newly synthesized fibrinogen on its way through the endoplasmic
reticulum and the Golgi to the exterior of the cell. Again the
stimulatory effects of the Ac1–26 peptide are somewhat more pronounced
than that of fMLP used at 103-fold lower
concentration, and thus to some extent differ from the situation in
neutrophil activation (4). In contrast to the F-actin
increase, the induction of fibrinogen expression is a rather long-term
effect elicited by fMLP and Ac1–26. Induction is clearly visible after
incubation with the ligands for 20 h (Fig. 2), whereas after
8 h the increase in fibrinogen synthesis is less robust and not
yet statistically significant (not shown). Fibrinogen synthesis could
be regulated by intermediates produced over the course of the 20 h
following FPR activation, e.g., acute-phase cytokines known to be
produced following FPR activation in human astrocytoma cells
(15). Therefore, we determined by ELISA the levels of IL-6
and IL-1 in the supernatants collected following FPR activation. No
increase in the secretion of these cytokines was observed, indicating
that the effects of fMLP and Ac1–26 on fibrinogen synthesis are not
mediated by the secondary release of such cytokines (data not
shown).
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In A549 cells, annexin 1 expression had been reported to be
up-regulated by IL-6 and dexamethasone (17). Moreover,
although signaling through a different receptor than FPR, IL-6 also
elicited a stimulatory effect on acute-phase protein synthesis that was
comparable with that of fMLP and Ac1–26 in our experiments. Thus, we
analyzed next whether annexin 1 levels themselves could also be
regulated by FPR activation. Cells were treated for 20 h with the
FPR agonists fMLP or Ac1–26, respectively, and the annexin 1 content
was then compared with that of nontreated or IL-6-treated cells by
immunoblotting of total cell lysates (Fig. 3). Although annexin 1 is constitutively
and abundantly expressed in untreated cells, incubation with IL-6
increased annexin 1 protein levels. Similarly, both fMLP and Ac1–26
signaling through the FPR triggered an increase in annexin 1.
Densitometric comparison of annexin 1 immunoreactive bands in the
differently treated cells revealed an almost 2-fold increase following
IL-6 induction, whereas fMLP and the annexin 1 peptide up-regulated
annexin 1 by 20 and 40%, respectively.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Activation of the FPR in A549 cells by both fMLP and the annexin 1 peptide triggered an increased production of acute-phase proteins. During inflammation, the acute-phase response is accompanied by a marked change in the concentrations of many plasma proteins. These so-called acute-phase proteins are modulated by inflammation-associated cytokines (26), with IL-6 being a chief stimulator inducing all of the type II acute-phase proteins (26, 27). Although the liver is the primary site of fibrinogen synthesis, basal fibrinogen expression has been documented in extrahepatic tissues and epithelial cells. Moreover, in cultured A549 cells, fibrinogen is up-regulated in response to IL-6 and dexamethasone in a manner similar to that of liver epithelial cells (16). Both the exogenous (fMLP) and, perhaps more importantly, the endogenous FPR ligand Ac1–26 trigger an increase in fibrinogen biosynthesis as does the acute-phase cytokine IL-6. Finally, we show that in A549 cells, annexin 1 itself can be up-regulated by its own exogenously applied peptide Ac1–26, most likely signaling through the FPR. This could suggest a possible autocrine mechanism and, in accordance with the reported elevation of annexin 1 expression by IL-6 and dexamethasone (17), could indicate that annexin 1 is itself a class II acute-phase protein.
Taken together, our results show that the FPR is expressed in the lung epithelial cell line A549 and that it can be triggered by the prototype bacterial ligand fMLP as well as the novel endogenous ligand Ac1–26. The activated receptor not only signals to the cytoskeleton, but also seems to be involved in the regulation of acute-phase proteins. Thus, the novel FPR ligand annexin 1 could serve as the long postulated endogenous ligand of the FPR in nonmyeloid cells. However, the effects elicited by Ac1–26/FPR signaling are not as drastic as those observed for IL-6 activation of its cognate receptor. This could be expected, however, if the Ac1–26/FPR system were involved in chronic inflammatory processes or a modulation of an ongoing inflammation and/or wound healing after tissue damage. Furthermore, the increased annexin 1 expression upon stimulation of the FPR by exogenous annexin 1 suggests an autoregulatory mechanism controlling the annexin 1 action during such inflammatory processes.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Volker Gerke, Center for Molecular Biology of Inflammation, Institute for Medical Biochemistry, von Esmarch-Strasse 56, 48149 Münster, Germany. E-mail address: gerke{at}uni-muenster.de
3 Abbreviation used in this paper: FPR, formyl peptide receptor.
Received for publication December 11, 2000. Accepted for publication May 20, 2002.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and dexamethasone. Immunology 79:236.[Medline]
1-antitrypsin by alveolar epithelial cells. FEBS Lett. 346:171.[Medline]
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